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Identification of the molecular mechanism of insulin-like growth factor-1 (IGF-1): a promising therapeutic target for neurodegenerative diseases associated with metabolic syndrome

Cell & Bioscience volume 13, Article number: 16 (2023) Cite this article

Abstract

Neurodegenerative disorders are accompanied by neuronal degeneration and glial dysfunction, resulting in cognitive, psychomotor, and behavioral impairment. Multiple factors including genetic, environmental, metabolic, and oxidant overload contribute to disease progression. Recent evidences suggest that metabolic syndrome is linked to various neurodegenerative diseases. Metabolic syndrome (MetS) is known to be accompanied by symptoms such as hyperglycemia, abdominal obesity, hypertriglyceridemia, and hypertension. Despite advances in knowledge about the pathogenesis of neurodegenerative disorders, effective treatments to combat neurodegenerative disorders caused by MetS have not been developed to date. Insulin growth factor-1 (IGF-1) deficiency has been associated with MetS-related pathologies both in-vivo and in-vitro. IGF-1 is essential for embryonic and adult neurogenesis, neuronal plasticity, neurotropism, angiogenesis, metabolic function, and protein clearance in the brain. Here, we review the evidence for the potential therapeutic effects of IGF-1 in the neurodegeneration related to metabolic syndrome. We elucidate how IGF-1 may be involved in molecular signaling defects that occurs in MetS-related neurodegenerative disorders and highlight the importance of IGF-1 as a potential therapeutic target in MetS-related neurological diseases.

Introduction

Metabolic syndrome (MetS) is a collection of metabolic abnormalities, including hypertension, central obesity, and atherogenic dyslipidemia [1]. MetS significantly increases the risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease [2]. Additionally, emerging evidences have shown that MetS can affect the central nervous system (CNS) diseases through various mechanisms [3]. Several studies suggest that MetS is associated with various neurodegenerative disorders, including Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD) [4,5,6,7,8].

Synaptic and glial dysfunction with aberrant networks between these cells is a hallmarks of neurodegenerative diseases (NDDs) [9]. Many NDDs can be classified as pyramidal and extrapyramidal, with motor and behavioral or cognitive impairments being the most common clinical manifestations [10]. Various molecular and cellular pathologies are associated with these NDDs, including oxidative stress, mitochondrial dysfunction, calcium (Ca2+) influx, glutamate toxicity, proteolytic stress, protein aggregation, neuroinflammation, and neuronal death [11, 12]. Over the past two decades, there has been a significant increase in evidence demonstrating the potent neuroprotective effects of neurotrophic factors (NTFs) on NDDs [13]. NTFs are crucial for CNS development and play vital roles in neurogenesis, neuronal cell migration, and CNS cell survival [14]. Recent research has focused on NTFs to understand their role in the etiology and as potential therapy for various neurological diseases. One of the major NTFs is insulin-like growth factor-1 (IGF-1), a peptide hormone (7649 Da and 70 amino acids) that belongs to the insulin-like hormone superfamily that include insulin, IGF-1, and IGF-2 [15].

The molecular signalling of IGF is highly evolutionarily conserved. IGF1 can act through autocrine, paracrine and endocrine mechanisms to regulate cellular growth, differentiation and proliferation [16]. The IGF system consists of six IGF binding proteins (IGFBPs) and two growth factors (IGF-1 and IGF-2) along with their cognate insulin growth factor receptors (IGF-1R, IGF-2R) [15]. The majority, up to 99% of IGF-1 binds to circulating IGFBP-1[17]. In the brain (hippocampus, cortex, olfactory lobes, cerebellum, and amygdala), IGF-1 binds to IGFBP-2, -4, and -5b [18]. In adults, IGF-1 is produced primarily in the liver and to a lesser extent in the hippocampus, cerebellum, and subventricular zone-olfactory bulb (SVZ-OB) under stimulation of growth hormone (GH) [19]. GH regulates neurogenesis and neuronal plasticity [20]. IGF-1 exerts its actions by binding and activating its membrane receptors, which are receptor tyrosine kinases [16]. After IGF-1 binds to its ligand, a series of phosphorylation events leading to activation of insulin receptor substrates, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase/protein kinase B (PI3K-Akt) lead to various intracellular processes [21]. A recent study has focused on the role and therapeutic potential of IGF-1 in the CNS to improve brain function and complex mechanisms of the CNS in MetS-induced neurodegeneration [22]. Herein, we focus on the potential therapeutic effects of IGF-1 in NDD associated with MetS and the molecular mechanisms underlying its pharmacological effects.

IGF-1 in the CNS

IGF-1 can cross the blood brain barrier (BBB) and enter CSF, and perform a number of important functions of the CNS, including neurogenesis and neuroprotection, through autocrine/paracrine or endocrine effects. It affects metabolic regulation in the CNS, promotion of other nerve growth factors, clearance of aggregate proteins, and angiogenesis [23,24,25] (Fig. 1). High levels of IGF-1 are found in the CNS during early stages of organogenesis, which promotes brain derived growth factor (BDNF) and other neutrotropic factors that play important roles during brain development [26, 27]. Another study demonstrated that IGF-1 administration increased overall BDNF and decreased expression of interleukin (IL)-1β, TNF-α, nitric oxide synthase (iNOS), and glial fibrillary acidic protein (GFAP) in the whole brain [28]. IGF-1/IGF1R signaling has also been associated with Schwann cell (SC) survival, migration, proliferation, and myelination [29, 30]. In-vitro experiments with glial cells, oligodendrocytes, brain explants, and adult stem cells have revealed that IGF-1 promotes myelination, differentiation and mitogenesis [31]. Furthermore, IGF-1 can promote oligodendroglial cells to survive by inhibiting caspase-3 [31]. IGF-1/IGF-1R knockout mice showed decreased brain size, loss of myelination, and cognitive decline, whereas overexpression of IGF-1 resulted in increased brain size and myelination [32]. Moreover, IGF-1 regulates neural stem cell proliferation by promoting replicative lifespan and shortening all cell cycle lengths, particularly the G1/S transition [33]. Numerous clinical studies have demonstrated that IGF-1/IGF-1R mutations are associated with mental retardation and microcephaly [34, 35] (Table 2). Lichtenwalner et al., reported that altered levels of IGF-1 negatively affect neurogenesis and synaptic plasticity, particularly in the hippocampus [36]. In an in-vivo models, IGF-1 influences adult dentate gyrus development by increasing the number of granule neurons and thus increasing the dentate granule cell layer [37, 38]. IGF-1-RIT1-Akt-Sox2 pathway plays a key role in IGF-1-induced neurogenesis, cellular proliferation, and gene expression in hippocampus neurons [39]. IGF-1 can also influence neuronal excitability and glutamate system in brain [40]. In various in-vivo and in-vitro studies, exogenous administration of IGF-1 mediated has been shown to increase glucose utilization, release acetylcholine from neurons, activate N-methyl-D-aspartate receptor (NMDA), protect the cerebromicrovascular environment, and maintenance of synaptic structure and function [36, 41,42,43,44,45]. IGF-1 can also interact with NMDA receptors to promote synaptic function and facilitate PI3K/glutamatergic transmission in the hippocampus [46,47,48,49]. Kelsch et al. showed that during hippocampal maturation, K+/Cl− outward transport is mediated by IGF-1/PI3K pathway [50]. Furthermore, IGF-1 increased presynaptic facilitation by activating p38/MAPK to modulate K+ channel activity [51, 52]. However, IGF-1R is highly expressed in cerebral plexus (CP), hypothalamus, thalamus, amygdala, and hippocampus/parahippocampal gyrus. Given that these regions are critically linked to cognition, it is compelling that IGF-1 and IGF-1R deficiencies lead to cognitive impairment [46, 53]. The transcriptional regulator CREB (cAMP response element binding protein) is a critical regulator of axonal growth and neuronal plasticity that is important for neuroprotection and cognition preservation [54]. In many cell types, IGF-1 enhances CREB phosphorylation and controls CRE-containing genes, such as c-Fos and B-Cell Leukemia/Lymphoma 2 (Bcl-2) [55]. Neuronal survival is also linked to the MAPK-CREB signaling pathway. By phosphorylating Bad and CREB, activated ribosomal protein S6 kinase beta (RSKs) can inhibit apoptosis [56, 57]. Also, IGF-1 can suppress various proapoptotic signals through regulation of multiple downstream targets [55]. As such, IGF-1 is an essential factor in maintaining neuronal homeostasis, and identifying the role of IGF-1 in the brain is important for finding clues to effective treatment targets for NDDs (Fig. 1).

Fig. 1
figure 1

Schematic image on physiological and pathological action of IGF-1. IGF-1 in the healthy brain maintains the cerebrovascular microenvironment and BBB/CP integrity, regulates inflammation in microglia, and facilitates synaptic communication and cognition by acting on ionic channels and neurotransmitters. In Metabolic syndrome (MetS) related brain, both systemic and local deficiency of IGF-1 shows the altered cerebrovascular microenvironment/disturbed BBB/CP integrity, increased the deposition of α- Synuclein/Tau/Aβ/HTT proteins cause impaired neuroinflammatory action, neurotransmitter release, synaptic plasticity, and cognition which may lead to neurodegenerative diseases (AD/PD/HD)

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Therapeutic applications of IGF-1 in neurological diseases

Several recent studies highlight the pleiotropic actions of IGF-1 in neurons [29, 39, 42]. Tables 1 , 2 , and 3 describe the consequences of IGF-1 deficiency and the therapeutic effects of IGF-1 in experimental and clinical studies of neurological diseases. Our focus in this section is the effect of IGF-1 on neurodegenerative diseases, specifically AD and PD.

Table 1 IGF-1-deficient-induced neurological disease
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Table 2 Therapeutic applications of IGF-1 in neurological diseases
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Alzheimer’s disease (AD)

AD is characterized by a progressive cognitive decline affecting around 25 million individuals worldwide [58], and causes difficulties in learning and memory, language, and executive motor function [59]. AD is generally thought to be caused by amyloid-beta (Aβ) accumulation and plaque formation in the brain, a pathology known as the “amyloid hypothesis” [60]. There are evidences that IGF-1 may prevent age-related cognitive decline [48]. Several studies have shown that low IGF-1 levels are associated with AD (Table 1).

Along with the canonical trophic role of IGF-1, it has also been shown to exert neuromodulatory effects through regulating neurotransmitter release (Fig. 2). Emerging research shows that glutaminergic neurotransmission through glutamate receptor NMDA plays a major role in learning and memory [61,62,63]. NMDA is also involved in the induction of long term potentiation (LTP) [63, 64] and can regulate synaptic plasticity [65]. Sonntag et al. reported that chronic administration of IGF-1 increases the density of NMDA receptors (NMDAR1, NMDAR2A, and R2B subunits) in the hippocampus, dentate gyrus and cortical areas, which are mainly involved in learning and memory [48]. Trejo et al. showed that IGF-1 restores cognitive function by attenuating the deposition of Aβ in an experimental model of AD [25].

Table 3 Therapeutic action of IGF-1 on MetS-related neurological diseases
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Fig. 2
figure 2

Schematic image on molecular actions of IGF-1 in CNS cells. A Blood–brain barrier (BBB)/choroid plexus (CP) and glucose homeostasis in astrocytes: IGF-1 binds to the astrocytic cell membrane's IGF-1 receptors, activates the PI3K/Akt pathway, and recruits the GLUT transporters, which then begins the uptake of glucose into the cell via GLUT transporters. B Neuroinflammation caused by microglia: When IGF-1 binds, it stimulates the polarization of the macrophages via TLR4 increasing the production of IL-1β, TNF-α, iNOS, and iba-1 while decreasing ROS and activating NF-κB/NLRP3 signaling. C PI3K/Akt/mTOR/NF-κB/CREB/MAPK signaling regulation in neurons: The PI3K/Akt signaling cascades are initiated when IGF- binds, phosphorylating the GSK, NF-κB, Bad, Caspase 9, and FOXO proteins. These additional phosphorylation result in the nuclear phosphorylation of c-fos and Bcl2, which prevents apoptosis, promotes axon development, and enhances neural plasticity. D Regulation of mitogenesis in oligodendrocytes and myelination in Schwann cells: In oligodendrocytes, IGF-1 inhibits the caspase-2 activity, shortening the G1/S cell cycle transition. In Schwann cells, IGF-1 facilitates myelination via increasing the myelinated proteins such as PLP, MBP, and NDF. E Regulation of ionic channels, synaptic function, and neurotransmitter release: IGF-1 regulates the Na+/Ca2+/K+ channels to increase the Ca2+ influx and maintain the Na+ concentration. In neurotransmitters, IGF-1 activates the NMDAR/KAR/AMPA receptors which regulate the acetylcholine, GABA, glutamate, and dopamine synthesis and release

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Furthermore, IGF-1 has been implicated in several ways to affect synaptic plasticity [66, 67]. IGF-1 may promote synaptic plasticity and transmission in minutes or persist for several hours to increase neuronal differentiation and survival (Fig. 2). Several types of neurons become more excitable in response to IGF-1 [68]. Studies have shown that the systemic administration of IGF-1 improves synaptic complexity and neurogenesis in the hippocampus [36, 69]. Moreover, IGF-1 in cultured hippocampal neurons increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) for a short or long term, but had no effect on miniature excitatory postsynaptic currents (mEPSCs) or spontaneous inhibitory postsynaptic currents (sIPSCs). Indeed, the excitatory transmissions has been shown to be mediated by MAPK pathways [68]. Furthermore, IGF-1 inhibited synaptic transmission by increasing the frequency of sIPSCs in response to Aβ- reduction in sIPSC frequency [70]. This suggests that IGF-1 increased glutamate release at presynaptic sites or the functional excitability of synaptic contacts, but had no effect on non-NMDA or NMDA receptors.

In the CA1 region of the hippocampus, des (1–3)-IGF-1 increased the field excitatory postsynaptic potentials (fEPSPs), EPSCs, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated postsynaptic exocytosis/endocytosis mechanism [71]. Des-IGF-1 affects glutamate receptor AMPAR binding protein (GRIP), N-ethylmaleimide-sensitive fusion protein (NSF), stargazin, and proteins that interact with C-kinase-1, which influence AMPA receptor anchoring, surface translocation, and synaptic targeting [72]. Furthermore, activation of the IGF-1R facilitates the AMPA synaptic mechanism by increasing intracellular calcium mobilization at the synapse [67]. These findings suggest that IGF-1 is important for regulating the AMPA receptors involved in LTP and cognition. IGF-1 modulates synaptic plasticity primarily by regulating ion channels (Ca2+-binding proteins), neurotransmitter secretion, and neuronal arborization. Also, IGF-1 phosphorylates and activates the α-1 subunit of the L-type Ca2+ channel through the PI3K pathway [73]. The Na+/Ca2+ exchanger (NCX) is a neuronal reciprocal Ca2+ transporter that promotes neuroprotection. This is mediated by IGF-1 by increasing the NCX-induced inward and decreasing the outward current [74]. Accordingly, systemic IGF-1 modulates the electrophysiological properties of target neurons. IGF-1 blocks transient A-type K+ currents and increases high-voltage-activated Ca2+ currents, while keeping low-voltage-activated Ca2+ and Na+ current constant [75].

Other glutamate receptors, including kainate receptors (KARs) and metabotropic glutamate receptors, can control long-term and short-term synaptic plasticity [76, 77]. KARs can be found on the gamma-aminobutyric acid (GABAergic) and glutamatergic presynaptic terminals [78]. IGF-1 increases the potency of kainate-dependent currents in cerebellar granule neurons and modulates Ca2+, Cl−, and K+ channels by PI3K-dependent pathway, but not MAPK dependent pathway [73, 79]. Although IGF-1 can stimulate neurogenesis and promote cognition in short-term, some studies have demonstrated that chronic administration of IGF-1 causes side effects such as accelerated aging, cancer development, and decreased lifespan [80, 81]. Thus, fine tuning these potential hormonal effects remains an important challenge to addressed.

Researchers have reported that reduced serum IGF-1 levels are associated with AD and decreased brain volume in clinical studies [82]. A study by Carro et al. showed that systemic administration of IGF-1 to mice deficient in hepatic IGF-1 resulted in increased serum IGF-1 levels, decreased the Aβ bodies in brain, and increased uptake by Aβ bodies in CSF facilitated by transthyretin and albumin [83]. Kimoto et al. also reported that reduced IGF-1 in serum is associated with cognitive deficits in subjects with AD [84]. IGF-1 can prevent AD development by altering several signaling proteins including rat sarcoma virus (Ras), forkhead box O (FoxO), and MAPK and their pleiotropic actions [85]. The IGF-1R belongs to the tyrosine receptor kinase family that controls many downstream targets, notably MAPK, Akt, Ras, PI3K, and the binding proteins growth factor receptor-bound protein 2 (Grb2) and Shc (Src homology 2 domain containing) transforming protein 1) [86]. PI3K/Akt is a well-known cascade induced by stimulation of IGF-1R [87]. Activated PI3K phosphorylates PIP2 to PIP3, which triggers the phosphorylation of P3-dependent kinase-1/2 (PDK-1/2) at Thr308 and Ser473 residues, resulting in Akt to be recruited to the plasma membrane (Fig. 2). The activated Akt can in turn phosphorylate various target proteins involved in survival and differentiation pathways, including BCL2 associated agonist of cell death (Bad), GSk3, nuclear factor-κB (NF-κB), FoxO1, FoxO3a, and FoxO4 [88]. IGF-1 suppressed NF-κB signalling by upregulating miR-219a-2-3p and inhibiting YY1 gene expression, which is important for the activation of NF-κB signalling [89].

In AD, elevated levels of tumor necrosis factor-α (TNF-α) may play a significant role in exacerbating amyloidosis [90, 91], and IGF-1 attenuate amyloidosis by antagonizing TNF-α [83]. Recent researches have showed that altered CP function can exacerbate Aβ accumulation in the brain [73, 92], and numerous in-vitro studies have shown that IGF-1 can maintain tight junction stability in CP epithelial cells [92, 93]. On in-vitro study have also shown that IGF-1 maintains tight junction stability in CP epithelial cells [93]. Therefore, IGF-1 can modulate various ion channels and molecular signlaing pathways to attenuate inflammation and promote BBB-CP stability to prevent Aβ deposition and cognitive decline in AD.

Parkinson’s disease (PD)

PD is the second common neurological diseases after AD, with a high incidence among adults in their 50s and 60s [94]. The neuropathological hallmarks of PD are a neuronal cell damage in substantia nigra of brain, leading to insufficient secretion of dopamine and accumulation of intracellular inclusions including α-synuclein aggregates [95]. Effective treatment for individuals with PD is challenging due to the lack of pharmacological options and adverse effects such as dyskinesia related to the use of levodopa.

In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, IGF-1R deficiency resulted in enhanced dopaminergic neuronal death [96]. Several clinical studies showed that low serum IGF-1 level was present in individuals with PD [97,98,99]. A cleaved form of IGF-1, glycine-proline-glutamate (GPE), prevents the death of tyrosine hydroxylase (TH) immunopositive neurons, and restores TH immunoreactivity in the substantia nigra compacta (SNc) and the striatum of a 6-hydroxydopamine (6-OHDA)-induced PD model [100].

Administration of cleaved IGF-1 (GPE-3 mg/kg, intraperitoneally [i.p]) also improved motor function and decreased dopaminergic neuronal loss in the 6-OHDA model [101]. Similarly, treatment with IGF-1 in 6-OHDA-induced PD model of ovariectomized rats resulted in increased motor function of the forelimbs, reduced loss of SNc neurons, and normal immunoreactivity of TH in the striatum and dopaminergic fibers [102]. In another study, IGF-1 significantly upregulated the survival of human neural progenitor cells in the 6-OHDA-induced PD model [103]. Alessandro et al. found that after depolarization, dopaminergic neurons secrete IGF-1, which can stimulate dopamine release in the ventral midbrain [104]. The neuroprotective effects of IGF-1 on PD are mediated by PI3K/Akt signaling rather than MAPK/ERK pathway [105]. Wang et al. reported that IGF-1 inhibits the activation of c-Jun N-terminal kinases (JNK) via the PI3K/AKT/GSK3β (Glycogen synthase kinase 3β) pathway, and 1-methyl-4-phenylpyridine ion (MPP+)-induced apoptosis [106]. Therefore, IGF-1 prevents the loss of dopaminergic neurons and improves motor function in PD model by upregulating the PI3K/AKT/GSK3/MAPK/ERK pathway.

Metabolic syndrome and neuropathology

MetS is observed concurrently with several abnormalities including central obesity, hyperglycemia, hypertension, dyslipidemia, inflammation and thrombotic states [60]. The International Diabetes Federation criteria for MetS included a fasting blood glucose levels > 5.6 mmol/L (100 mg/dL); blood pressure > 130/85 mmHg; blood triglyceride levels > 1.7 mmol/L (150 mg/dL); HDL cholesterol levels < 1.0 mmol/L (40 mg/dL) for men and < 1.3 mmol/L (50 mg/dL) for women, and waist circumference > 94 cm (men) or > 80 cm (women) [107, 108]. Considering recent evidences, MetS is a major risk factor for type 2 diabetes (T2D) and cardiovascular disease, as well as an emerging major risk factor for NDDs.

Accumulating evidence supports that MetS plays a major role in the development of cognitive impairment [109]. MetS is also known to induce oxidative stress and inflammation, which can lead to cognitive decline by reducing the number and function of hippocampal neurons [109,110,111,112]. Furthermore, studies investigated the relationship between circulating IGF-1 concentrations and metabolic syndrome. This review focused on the neuroprotective effects of IGF-1 in MetS-related NDDs.

Diabetes mellitus-related neurodegenerative disease

Diabetes mellitus is characterized by hyperglycemia due to complex pathogenic mechanisms involving widespread insulin resistance and impaired insulin production. Type 1 diabetes (T1D) is an autoimmune disease that causes damage to pancreatic β-cells. The most common type, type 2 diabetes (T2DM), is characterized by dysfunctional β cells and insulin resistance [113]. Scientific evidences has demonstrated a substantial association between diabetes (both T1D and T2D) and cognitive decline leading to dementia in animal models and humans [29, 49, 114, 115].

One study shows that 56% of AD dementia area associated with T2D [116]. In fact, the significance of the link between T2D and AD is now defined by the term “type 3 diabetes”, which describes a subset of diabetic patients who develop AD dementia [117,118,119]. In T2D, insulin resistance and altered IGF-1/IGF-1R signaling are associated with cognitive decline, Aβ production, tau hyperphosphorylation, proinflammatory marker’s expression, oxidative stress, and dyslipidemia [120, 121]. Rui-Hua et al. found that decreased serum IGF-1 levels were associated with T2D-associated cognitive decline in clinical trials [122]. Another study showed that subjects with mild cognitive impairment with T2D had a reduced serum IGF-1/IGFBP-3 molar ratio [123]. Aksu et al. showed that reduced IGF-1 induces anxiety-like behavior and reduced blood flow to the prefrontal cortex in streptozotocin (STZ)-induced diabetic rats [124]. In addition, Jing et al. showed that maternal hyperglycemia reduces the expression of IGF-1, resulting in delayed fetal dendrite development in STZ-induced rats [125].

Hyperglycemia is associated with a lack of neurotrophic signaling that can lead to mitochondrial dysfunction of SC [126]. Chronic hyperlgycemia can lead to vacuolization and atrophy or degeneration of myelinated nerve fibers [127]. Myelinated nerve fibers (Aδ-type afferent fibers) are susceptible to dysfunction when their conduction velocity changes [127]. Chu et al. reported that STZ-induced mice carrying an IGF-1 adeno-associated viral (AAV) vector showed reduced peripheral motor nerve fiber demyelination [128]. SC express IGF-1 receptor, and activation by IGF-1 stimulates myelination, attachment to axons, and migration [129]. Ping et al. found that in the cerebral cortex and brainstem, IGF-1 increased the expression of proteins essential for myelination, such as the proteolipid protein (PLP) and myelin basic protein (MBP)[130]. IGF-1 promotes Po induction, DMA synthesis, and DNA synthesis caused by neuro-differentiation factor isoforms in SC. These findings demonstrate that IGF can stimulate proliferation and differentiation in SCs [128].

IGF-1 forms the central core elements of astrocyte functions, such as the regulation of glucose uptake, glutamate transport, and protection against oxidative stress in the brain [44, 131, 132]. IGF-1R enters astrocytes by binding to astrocyte glucose transporter 1 (GLUT1) via the low-density lipoprotein receptor-related protein-1 (LRP1) and scaffolding protein GIPC PDZ domain containing family, member 1 (GIPC1) (Fig. 2). These results suggest that IGF-1R modulates brain glucose metabolism by inhibiting the activity of GLUT1 in astrocytes [44]. Another study demonstrated that IGF-1 increased hypoxia-inducible factor-1 (HIF-1) and GLUT3 protein expression to maintain glucose homeostasis in neurons through PI3K/Akt/mTOR-dependent pathway [133]. These results imply that astrocytes may be important sensors of peripheral hormonal changes that connect the cerebral microenvironment to neurons to respond to endocrine signals. Therefore, therapeutic targets for improving astrocytic function include enhancement of IGFR signalling and mitochondrial function and glucose transport, which can alleviate age-related pathologies such as AD (Fig. 2).

On the other hand, in diabetic mice, IGF-1 expression was significantly decreased and pain, neuroinflammation, and M1 microglial polarization were increased [134]. Microglia are highly dynamic and can adopt wide-ranging responses to their environment to govern CNS homeostasis [135]. In brain injury, the microglia response switches from a proinflammatory M1 to an anti-inflammatory/reparative M2 for recovery. If this process is not regulated, excessive reactive nitrogen species (RNS), ROS, and inflammatory cytokines secreted by M1 phenotype microglia can cause neuronal damage [135,136,137]. IGF-1 is mainly produced by microglia, which is elevated during the inflammatory process [138, 139]. IGF1 as a pleiotropic hormone, signals macrophages to help various tissues develop and maintain homeostasis [140]. Sun et al. reported that IGF1R stimulates M1 polarization through toll-like receptor (TLR4)/NF-κB pathway in intracerebral haemorrhage (ICH) induced mice [141]. Furthermore, IGF-1 activates the PI3K/Akt/FoxO1 pathway without affecting TLR2/4 expression in an in vitro hyperglycemic study [142]. Wolters et al. demonstrated that IGF-1 does not produce cytokine itself, and regulates TLRs responsible for inflammatory effects during metabolic complications. Another study reported that TLR4 mutant mice fed HFD showed neurovascular protection by improving astrocytic vascular recovery and cerebromicroenvironement [143]. Similarly, Maria et al. reported the anti-inflammatory action of IGF-1 in astrocytes by IGF-1 gene therapy. Additionally, exogenous treatment with IGF-1 reduced TLR4 expression and reduced NF-κB activation in lipopolysaccharide-induced inflammatory response of astrocytes [144]. As a result of TLR activation, downstream signaling pathways such as PI3K/Akt/mTOR and MAPK are induced, and promote cytokines production through activation of the NF-κB signaling pathway. These downstream targets are shared by the IGF1 receptor and TLRs [145]. Lee et al. demonstrated that IGF-1 exerts anti-inflammatory action by downregulating the TLR4 signaling in skeletal muscle [146]. These findings suggest direct pro/anti-inflammatory actions of IGF-1 which regulates neuroinflammation and is involved in neuroprotection by maintaining the cerebromicroenvirontment, increasing the capillary density and microglial activation in neuroinflammation by TLR4 signaling (Fig. 2). These findings imply that decreased IGF-1 levels are directly related to cognitive impairment, and neuroinflammation, and suggest that therapeutic restoration of IGF-1 levels may improve cognitive function.

Obesity-related neuropathology

The prevalence of MetS has increased dramatically in the past decades, primarily due to significant lifestyle changes, including imbalance diet and physical inactivity [147]. According to recent estimates, around 2.1 billion people are overweight or obese [148]. Obesity has become a global epidemic with enormous medical, social, and economic burdens. Western diets are high in salt, processed carbohydrates and saturated fats, which negatively impact body mass and metabolism, including dyslipidemia, abdominal obesity, and T2D [149].

Obesity negatively affects CNS homeostasis and cognitive function [148, 150, 151]. The CNS and peripheral nervous system are fundamentally different in structure and function. And since both are prone to obesity-related dysfunction, this suggests a common pathway leading to the persistent disease progression through visceral fat. Also, a high body mass index (BMI) (> 30 kg/m2) has been recognized as one of the risk factors for PD [152, 153]. Obese individuals have fewer striatal dopamine receptors than non-obese individuals. Obesity has a deleterious influence on motor function and manual dexterity [154, 155].

Additionally, Bhat et al., reported that a high-fat/high-cholesterol diet can promote cognitive decline and brain dysfunction [156]. High fat diet (HFD)-induced obesity altered the circulating IGF cascade and increased circulatory level of total IGF-1, IGF-2, free IGF-1, and IGFBP3 in rodent and clinical trials [157, 158]. However, insulin/IGF signaling (IIS) may be critical in diet-induced AD-like pathology. Tau phosphorylation and GSK3 activation mainly result from impaired IIS signaling in the brain [159, 160]. Naryan et al. reported that downregulated IIS increased tau phosphorylation, promoted GSK activation, and decreased insulin receptor substrate-1 (IRS1), phospho-Akt, drebrin, and postsynaptic density (PSD95) resulting in cognitive impairment in the HFD model [156]. Based on these studies, obesity has been identified as one of the major causes for the development of neuropathology, and altered insulin/IGF signaling contributes to obesity-related AD.

Cardiovascular disease-related neuropathology

Hypertension is defined as systolic blood pressure (SBP > 140 mmHg) or diastolic blood pressure (DBP > 90 mmHg), and is found in more than one billion people worldwide [161]. Hypertension plays a cardinal role in the progression of cerebromicrovascular injury and vascular cognitive impairment [42]. Some studies suggest that changes in cerebral microcirculation play a crucial role in age-related cognitive decline [162,163,164]. Furthermore, circulating IGF-1 has been shown to be a critical vasoprotective factor that declines with age, and its deficiency can accelerate vascular aging [165]. IGF-1 deficiency is also associated with an increased risk of early atherosclerosis and cerebrovascular disease [165]. Tarantini et al. reported that IGF-1 deficiency accelerates BBB damaged by hypertension, altered capillary morphology in cortical areas, and exacerbates neuroinflammation [42]. Additionally, HFD-fed GH/IGF-1 deficient animals showed glucose intolerance, increased body fat content, oxidative stress, activated inflammatory markers (TNF-α, ICAM-1), and endothelial dysfunction resulting in cerebrovascular damage [166].

Cerebromicrovascular rarefaction leads to decreased cerebral blood flow, which can lead to neurological dysfunction by lowering metabolic factors required for neural signalling [167]. Angelini et al. has been shown that decreased IGF-1 reduced acetylcholine release in the hippocampus, and ultimately led to cognitive decline in hypertensive subjects [43]. Sonntag et al. also showed that IGF-1 influences learning and memory function by regulating K+-induced acetylcholine release in the cortex and hippocampus [48]. Endothelium-derived nitric oxide (NO) is a key regulator of microvascular endothelial cell survival and a negative modulator of vascular endothelial growth factor (VEGF) signaling. IGF-1 deficiency impairs endothelial NO bioavailability through elevation of NO breakdown due to increased generation of reactive oxygen species (ROS) and downregulation of endothelial nitric oxide synthase (eNOS) [168, 169].

Other factors contributing to hypertension-related vascular dementia are aging and mitochondrial dysfunction. Reduced mitochondrial biogenesis, neuronal and astrocyte function, and increased ROS are important determinants of aging and neurodegeneration [170,171,172,173]. Mitochondria consume about 90% of cellular oxygen through cellular respiration, resulting in a constant stream of free radicals that, if mismanaged, cause long-term oxidative stress and damage [174,175,176]. IGF-1 reduces the pro-oxidant protein thioredoxin-interacting protein 1 and normalizes ROS levels (Fig. 2). Furthermore, IGF-1 can provide neuroprotection from oxidative danage by interacting with trophic factors secreted by astrocytes in conjunction with H2O2, such as stem cell factor (SCF) [132].

The IGF-1 pathway is a major determinant of aging. The rate of aging also depends on the amount of IGF-1 and the density of its receptors [177]. There is a considerable increase in neural MAPK phosphorylation with aging along with a decrease in Calcium/Calmodulin-Dependent Protein Kinase IIa (CaMKIIa) levels. Changes in the phosphorylation of synaptic kinases (CaMKII and MAPK) involved in the regulation of long-term potentiation may be related to IGF-1/IGF-1R signalling [158]. IGF-1 was recently identified as belonging to a new class of ion channel modulators with rapid response (Fig. 2). IGF-1 regulates N-type and L-type Ca2+ channels required for neuronal survival and release of neurotransmitters [178]. L-type Ca2+ channels (CaV1.2 and CaV1.3) regulate a wide range of neurological functions [179, 180]. IGF-1 can rapidly activate CaV1.3 by modulating IGF-1R, which phosphorylates and activates CaMKII (CaV1.3a and CaV1.3b at the C termini sites, resulting in inositol trisphosphate (IP3)-induced Ca2+ release [181]. CaV1.3 phosphorylation by IGF-1 at S1486 residue induces a left-shifted current–voltage that regulates CREB. Excitatory neurotransmitter-induced signaling pathways in the hippocampus are influenced by IGF-1-induced CREB/CaV1.3 signaling. IGF-1 increased Ca2+ influx through L-type Ca2+ channels and increased CaMK-IV activity, which reduced the expression of CCAAT enhancer-binding proteins (C/EBPβ) [182].

IGF-1 has been shown to improve mitochondrial function and transmembrane potential in a HFD-fed obese mouse model [183]. IGF-1 contributes considerably to vascular health and protects cells from vascular damage and neuropathological problems [169].

Limitations and future perspectives

Although substantial research has been conducted on the IGF-1 signaling pathway in the past decades, the precise relationship between IGF-1 and cognition remains unclear. Although most studies using animal models have demonstrated neuroprotective effects, human studies have been less conclusive.

Despite its potential therapeutic significance outlined in this review, the long-term benefits of IGF-1 remain controversial. Various side effects have been reported with chronic IGF-1 therapy, including pain at the injection site and lipohypertrophy, headache, hypoglycemia, papilloedema, cataract, neoplasia, renal hypertrophy, and facial nerve palsy [80, 184]. Few studies have shown that overexpression of IGF-1 increases cancer risk through activation of the IRS/Akt/MAPK pathway [31, 80, 81, 120, 185]. Also, Ter Braak et al. mentioned that chronic administration of IGF-1 and its analogue promotes mammary tumor development in the p53R270H/+WAPCre mouse model [186]. Studies have shown that the IGF signaling pathway is not only involved in tumorigenesis, but also contributes to resistance to standard cancer therapies [187]. Whether these unwanted effects may outweigh the benefits in the long run remains an important area of further study. This review has primarily focused on research over the past few decades on the metabolic effects of NDDs. More rigorous studies taking a genetic approach are needed to evaluate the role of IGF-1 and its precise downstream mechanistic targets that provide neuroprotection.

Conclusion

IGF-1 is a master regulator of protein, RNA and DNA synthesis and is involved in Ca2+ signaling that regulates synaptogenesis, neurite and glial (astrocytes, oligodendrocytes, schwann cells and microglia) proliferation and repair. Numerous studies have shown the neuroprotective effects of IGF-1. Thus, IGF-1 is a promising therapeutic option for the treatment of various neurological disorders through regulation of multiple neuroprotective signaling pathways, including Ras/Erk1/2, PI3K/MAPK/Akt/mTOR, Ca2+/CaMK II and IV, CREB, C/EBPβ, and GSK3B/NF-kB/NLRP3. It is also involved in regulating neuron and glial homeostasis through regulating ion channels, releasing neurotransmitters, and maintaining synaptic plasticity. Despite significant scientific advances supporting the restorative effects of IGF-1, the precise molecular pathways leading to its neuroprotective effects remain unclear and more studies are needed to accurately understand the role of IGF-1 in MetS-related neurological diseases.

Availability of data and materials

Not applicable.

Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid beta

AMPK:

AMP-activated protein kinase

AMPAR:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

APP:

Amyloid precursor protein

APLP1:

Paralogues amyloid precursor-like protein 1

ATP:

Adenosine triphosphate

AAV:

Adeno-associated viral

Bad:

BCL2 associated agonist of cell death

BBB:

Blood–brain barrier

BCL-2:

B-Cell leukemia/lymphoma 2

BDNF:

Brain-derived growth factor

BMI:

Body mass index

Ca2+ :

Calcium ion

CaMKII:

Calcium/calmodulin-dependent protein kinase II

CBF:

Cerebral blood flow

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CP:

Choroid plexus

Cl− :

Chloride ion

CREB:

CAMP response element binding protein

C/EBPβ:

CCAAT enhancer-binding proteins

DAYLs:

Disability-adjusted life-years

DA:

Dopamine

DCN:

Dorsal column nuclei

ERK1/2:

Extracellular regulated kinase 1/2

DM:

Diabetes mellitus

eNOS:

Endothelial nitric oxide synthase

fEPSPs:

Field excitatory postsynaptic potentials

FoxO:

Forkhead box O

GABA:

Gamma-aminobutyric acid

GBD:

Global burden of diseases

GCL:

Granule cell layer

GFAP:

Glial fibrillary acidic protein

GH:

Growth hormone

GSK3:

Glycogen synthase kinase

GRIP:

Glutamate receptor AMPAR binding protein

GPE:

Glycine-proline-glutamate

GLUT:

Glucose transporter

GIPC:

GIPC PDZ domain containing family: member 1

Grb2:

Growth factor receptor-bound protein 2

HD:

Huntington’s disease

HFD:

High-fat diet

HIF-1:

Hypoxia-inducible factor-1

hNPC:

Human neural progenitor cells

ICH:

Intracerebral haemorrhage

i.c.v:

Intracerebroventricular

IGF-1:

Insulin-like growth factor 1

IGF-1R/2R:

Insulin-like growth factor 1 receptor

IGF-1/RTK:

Insulin-like growth factor-1/receptor tyrosine kinase

IGFBP:

IGF binding protein

IIS:

Insulin/IGF signaling

i.p:

Intraperitoneally

iNOS:

Nitric oxide synthase

IP3:

Inositol trisphosphate

IRS1:

Insulin receptor substrate-1

IL:

Interleukin

JNK:

C-Jun N-terminal kinases

KARs:

Kainate receptors

LID mice:

Liver IGF-1 deficient mice

LID:

Levodopa-induced dyskinesia

LRP1:

Low-density lipoprotein receptor-related protein-1

LTP:

Long-term potentiation

MCI:

Mild cognitive impairment

MAPK:

Mitogen-activated protein kinase

MBP:

Myelin basic protein

mtDNA:

Mitochondrial DNA

MT-IGF-1:

Monocyte/macrophage-derived IGF-1

NCX:

Na+/Ca2+exchanger

NDDs:

Neurodegenerative diseases

NTF’s:

Neurotrophic factor

NMDA:

N-methyl-d-aspartate

MetS:

Metabolic syndrome

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MPP+ :

1-Methyl-4-phenylpyridine ion

NF-κB:

Nuclear factor-κB

mEPSCs:

Miniature excitatory postsynaptic currents

NSF:

N-ethylmaleimide-sensitive fusion protein

NO:

Nitric oxide

NVC:

Neurovascular coupling

K+ :

Potassium ion

PD:

Parkinson’s disease

PDK-1:

P3 dependent kinase-1

PI3K:

Phosphatidylinositol 3-kinase

PLP:

Proteolipid protein

PSD95:

Post synaptic density 95

Ras:

Rat sarcoma virus

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

RSKs:

Ribosomal protein S6 kinase beta

SC:

Schwann cell

SCF:

Stem cell factor

sEPSC:

Spontaneous excitatory postsynaptic current

sIPSCs:

Spontaneous inhibitory postsynaptic currents

SNc:

Substantia nigra compacta

Shc:

Src homology 2 domain containing-transforming protein 1

STZ:

Streptozotocin

SVZ-OB:

Subventricular zone-olfactory bulb

TH:

Tyrosine hydroxylase

TNF-α:

Tumor necrosis factor-α

TLR4:

Toll-like receptor 4

T2DM:

Type 2 diabetes mellitus

ZDF:

Zucker diabetic fatty

6-OHDA:

6-Hydroxydopamine

VaD:

Vascular dementia

References

  1. Nilsson PM, Tuomilehto J, Rydén L. The metabolic syndrome—what is it and how should it be managed? Eur J Prev Cardiol. 2019;26(2):33–46.

    Article  Google Scholar 

  2. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640–5.

    Article  CAS  Google Scholar 

  3. Van Dyken P, Lacoste B. Impact of metabolic syndrome on neuroinflammation and the blood–brain barrier. Front Neurosci. 2018;12:930.

    Article  Google Scholar 

  4. Offen D, Shtaif B, Hadad D, Weizman A, Melamed E, Gil-Ad I. Protective effect of insulin-like-growth-factor-1 against dopamine-induced neurotoxicity in human and rodent neuronal cultures: possible implications for Parkinson’s disease. Neurosci Lett. 2001;316(3):129–32.

    Article  CAS  Google Scholar 

  5. Niikura T, Hashimoto Y, Okamoto T, Abe Y, Yasukawa T, Kawasumi M, et al. Insulin-like growth factor I (IGF-I) protects cells from apoptosis by Alzheimer’s V642I mutant amyloid precursor protein through IGF-I receptor in an IGF-binding protein-sensitive manner. J Neurosci. 2001;21(6):1902–10.

    Article  CAS  Google Scholar 

  6. Herrero-Labrador R, Trueba-Saiz A, Martinez-Rachadell L, de Sevilla MEF, Zegarra-Valdivia JA, Pignatelli J, et al. Circulating insulin-like growth factor I is involved in the effect of high fat diet on peripheral amyloid beta clearance. Int J Mol Sci. 2020. https://doi.org/10.3390/ijms21249675.

    Article  Google Scholar 

  7. Wang F, Wang L, Wang Y, Li D, Hu T, Sun M, et al. Exogenous IGF-1 improves cognitive function in rats with high-fat diet consumption. J Mol Endocrinol. 2020;64(2):115–23.

    Article  CAS  Google Scholar 

  8. Duarte AI, Petit GH, Ranganathan S, Li JY, Oliveira CR, Brundin P, et al. IGF-1 protects against diabetic features in an in vivo model of Huntington’s disease. Exp Neurol. 2011;231(2):314–9.

    Article  CAS  Google Scholar 

  9. Kovacs GG. Molecular pathology of neurodegenerative diseases: principles and practice. J Clin Pathol. 2019;72(11):725–35.

    Article  CAS  Google Scholar 

  10. Dugger BN, Dickson DW. Pathology of neurodegenerative diseases. Cold Spring Harb Perspect Biol. 2017. https://doi.org/10.1101/cshperspect.a028035.

    Article  Google Scholar 

  11. Gan L, Cookson MR, Petrucelli L, La Spada AR. Converging pathways in neurodegeneration, from genetics to mechanisms. Nat Neurosci. 2018;21(10):1300–9.

    Article  CAS  Google Scholar 

  12. Dharshini SAP, Jemimah S, Taguchi YH, Gromiha MM. Exploring common therapeutic targets for neurodegenerative disorders using transcriptome study. Front Genet. 2021;12: 639160.

    Article  CAS  Google Scholar 

  13. Blesch A. Neurotrophic factors in neurodegeneration. Brain Pathol. 2006;16(4):295–303.

    Article  CAS  Google Scholar 

  14. Costales J, Kolevzon A. The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders. Neurosci Biobehav Rev. 2016;63:207–22.

    Article  CAS  Google Scholar 

  15. Laron Z. Insulin-like growth factor 1 (IGF-1): a growth hormone. Mol Pathol. 2001;54(5):311–6.

    Article  CAS  Google Scholar 

  16. Talia C, Connolly L, Fowler PA. The insulin-like growth factor system: a target for endocrine disruptors? Environ Int. 2021;147: 106311.

    Article  CAS  Google Scholar 

  17. Holly JM, Perks CM. Insulin-like growth factor physiology: what we have learned from human studies. Endocrinol Metab Clin North Am. 2012;41(2):249–63.

    Article  CAS  Google Scholar 

  18. Werner H, LeRoith D. Insulin and insulin-like growth factor receptors in the brain: physiological and pathological aspects. Eur Neuropsychopharmacol. 2014;24(12):1947–53.

    Article  CAS  Google Scholar 

  19. Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab. 2000;85(12):4712–20.

    CAS  Google Scholar 

  20. Frater J, Lie D, Bartlett P, McGrath JJ. Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: a review. Ageing Res Rev. 2018;42:14–27.

    Article  CAS  Google Scholar 

  21. Bondy CA, Cheng CM. Signaling by insulin-like growth factor 1 in brain. Eur J Pharmacol. 2004;490(1–3):25–31.

    Article  CAS  Google Scholar 

  22. Salzmann A, James SN, Williams DM, Richards M, Cadar D, Schott JM, et al. Investigating the relationship between IGF-I, IGF-II, and IGFBP-3 concentrations and later-life cognition and brain volume. J Clin Endocrinol Metab. 2021;106(6):1617–29.

    Article  Google Scholar 

  23. Okamoto N, Yoshino K, Kitagawa S, Fujii R, Hamada S, Ikenouchi A, et al. Association between serum insulin-like growth factor 1 levels and the clinical symptoms of chronic schizophrenia: preliminary findings. Front Psychiatry. 2021;12: 653802.

    Article  Google Scholar 

  24. Carro E, Trejo JL, Gerber A, Loetscher H, Torrado J, Metzger F, et al. Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis. Neurobiol Aging. 2006;27(9):1250–7.

    Article  CAS  Google Scholar 

  25. Trejo JL, Carro E, Torres-Aleman I. Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci. 2001;21(5):1628–34.

    Article  CAS  Google Scholar 

  26. Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003;349(23):2211–22.

    Article  CAS  Google Scholar 

  27. Juanes M, Guercio G, Marino R, Berensztein E, Warman DM, Ciaccio M, et al. Three novel IGF1R mutations in microcephalic patients with prenatal and postnatal growth impairment. Clin Endocrinol. 2015;82(5):704–11.

    Article  CAS  Google Scholar 

  28. Park SE, Dantzer R, Kelley KW, McCusker RH. Central administration of insulin-like growth factor-I decreases depressive-like behavior and brain cytokine expression in mice. J Neuroinflammation. 2011;8:12.

    Article  CAS  Google Scholar 

  29. Aghanoori M-R, Agarwal P, Gauvin E, Nagalingam RS, Bonomo R, Yathindranath V, et al. CEBPβ regulation of endogenous IGF-1 in adult sensory neurons can be mobilized to overcome diabetes-induced deficits in bioenergetics and axonal outgrowth. Cell Mol Life Sci. 2022;79(4):1–19.

    Article  Google Scholar 

  30. Chattopadhyay S, Shubayev VI. MMP-9 controls Schwann cell proliferation and phenotypic remodeling via IGF-1 and ErbB receptor-mediated activation of MEK/ERK pathway. Glia. 2009;57(12):1316–25.

    Article  Google Scholar 

  31. Cao Y, Gunn AJ, Bennet L, Wu D, George S, Gluckman PD, et al. Insulin-like growth factor (IGF)-1 suppresses oligodendrocyte caspase-3 activation and increases glial proliferation after ischemia in near-term fetal sheep. J Cereb Blood Flow Metab. 2003;23(6):739–47.

    Article  CAS  Google Scholar 

  32. Sun LY, Al-Regaiey K, Masternak MM, Wang J, Bartke A. Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice. Neurobiol Aging. 2005;26(6):929–37.

    Article  CAS  Google Scholar 

  33. Popken GJ, Hodge RD, Ye P, Zhang J, Ng W, O’Kusky JR, et al. In vivo effects of insulin-like growth factor-I (IGF-I) on prenatal and early postnatal development of the central nervous system. Eur J Neurosci. 2004;19(8):2056–68.

    Article  Google Scholar 

  34. Ashpole NM, Sanders JE, Hodges EL, Yan H, Sonntag WE. Growth hormone, insulin-like growth factor-1 and the aging brain. Exp Gerontol. 2015;68:76–81.

    Article  CAS  Google Scholar 

  35. Laron Z, Kauli R. Fifty seven years of follow-up of the Israeli cohort of Laron syndrome patients—from discovery to treatment. Growth Horm IGF Res. 2016;28:53–6.

    Article  Google Scholar 

  36. Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR. Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience. 2001;107(4):603–13.

    Article  CAS  Google Scholar 

  37. Åberg MA, Åberg ND, Hedbäcker H, Oscarsson J, Eriksson PS. Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci. 2000;20(8):2896–903.

    Article  Google Scholar 

  38. Cheng CM, Cohen M, Tseng V, Bondy CA. Endogenous IGF1 enhances cell survival in the postnatal dentate gyrus. J Neurosci Res. 2001;64(4):341–7.

    Article  CAS  Google Scholar 

  39. Mir S, Cai W, Carlson SW, Saatman KE, Andres DA. IGF-1 mediated neurogenesis involves a novel RIT1/Akt/Sox2 cascade. Sci Rep. 2017;7(1):3283.

    Article  Google Scholar 

  40. Trejo JL, Piriz J, Llorens-Martin MV, Fernandez AM, Bolós M, LeRoith D, et al. Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects. Mol Psychiatry. 2007;12(12):1118–28.

    Article  CAS  Google Scholar 

  41. Sonntag WE, Ramsey M, Carter CS. Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging. Ageing Res Rev. 2005;4(2):195–212.

    Article  CAS  Google Scholar 

  42. Tarantini S, Valcarcel-Ares NM, Yabluchanskiy A, Springo Z, Fulop GA, Ashpole N, et al. Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype. Aging Cell. 2017;16(3):469–79.

    Article  CAS  Google Scholar 

  43. Angelini A, Bendini C, Neviani F, Bergamini L, Manni B, Trenti T, et al. Insulin-like growth factor-1 (IGF-1): relation with cognitive functioning and neuroimaging marker of brain damage in a sample of hypertensive elderly subjects. Arch Gerontol Geriatr. 2009;49(Suppl 1):5–12.

    Article  CAS  Google Scholar 

  44. Fernandez AM, Hernandez-Garzón E, Perez-Domper P, Perez-Alvarez A, Mederos S, Matsui T, et al. Insulin regulates astrocytic glucose handling through cooperation with IGF-I. Diabetes. 2017;66(1):64–74.

    Article  CAS  Google Scholar 

  45. Tarantini S, Balasubramanian P, Yabluchanskiy A, Ashpole NM, Logan S, Kiss T, et al. IGF1R signaling regulates astrocyte-mediated neurovascular coupling in mice: implications for brain aging. GeroScience. 2021;43(2):901–11.

    Article  CAS  Google Scholar 

  46. Calvo D, Gunstad J, Miller LA, Glickman E, Spitznagel MB. Higher serum insulin-like growth factor-1 is associated with better cognitive performance in persons with mild cognitive impairment. Psychogeriatrics. 2013;13(3):170–4.

    Article  Google Scholar 

  47. Molina DP, Ariwodola OJ, Weiner JL, Brunso-Bechtold JK, Adams MM. Growth hormone and insulin-like growth factor-I alter hippocampal excitatory synaptic transmission in young and old rats. Age. 2013;35(5):1575–87.

    Article  CAS  Google Scholar 

  48. Sonntag WE, Bennett SA, Khan AS, Thornton PL, Xu X, Ingram RL, et al. Age and insulin-like growth factor-1 modulate N-methyl-d-aspartate receptor subtype expression in rats. Brain Res Bull. 2000;51(4):331–8.

    Article  CAS  Google Scholar 

  49. VanGuilder HD, Yan H, Farley JA, Sonntag WE, Freeman WM. Aging alters the expression of neurotransmission-regulating proteins in the hippocampal synaptoproteome. J Neurochem. 2010;113(6):1577–88.

    CAS  Google Scholar 

  50. Kelsch W, Hormuzdi S, Straube E, Lewen A, Monyer H, Misgeld U. Insulin-like growth factor 1 and a cytosolic tyrosine kinase activate chloride outward transport during maturation of hippocampal neurons. J Neurosci. 2001;21(21):8339–47.

    Article  CAS  Google Scholar 

  51. Nuñez A, Carro E, Torres-Aleman I. Insulin-like growth factor I modifies electrophysiological properties of rat brain stem neurons. J Neurophysiol. 2003;89(6):3008–17.

    Article  Google Scholar 

  52. Aimond F, Rauzier JM, Bony C, Vassort G. Simultaneous activation of p38 MAPK and p42/44 MAPK by ATP stimulates the K+ current ITREK in cardiomyocytes. J Biol Chem. 2000;275(50):39110–6.

    Article  CAS  Google Scholar 

  53. Deijen JB, Arwert LI, Drent ML. The GH/IGF-I axis and cognitive changes across a 4-year period in healthy adults. ISRN Endocrinol. 2011;2011: 249421.

    Article  Google Scholar 

  54. Yu XW, Oh MM, Disterhoft JF. CREB, cellular excitability, and cognition: implications for aging. Behav Brain Res. 2017;322(Pt B):206–11.

    Article  CAS  Google Scholar 

  55. Zuloaga R, Fuentes EN, Molina A, Valdés JA. The cAMP response element binding protein (CREB) is activated by insulin-like growth factor-1 (IGF-1) and regulates myostatin gene expression in skeletal myoblast. Biochem Biophys Res Commun. 2013;440(2):258–64.

    Article  CAS  Google Scholar 

  56. Merienne K, Pannetier S, Harel-Bellan A, Sassone-Corsi P. Mitogen-regulated RSK2-CBP interaction controls their kinase and acetylase activities. Mol Cell Biol. 2001;21(20):7089–96.

    Article  CAS  Google Scholar 

  57. Wiggin GR, Soloaga A, Foster JM, Murray-Tait V, Cohen P, Arthur JS. MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts. Mol Cell Biol. 2002;22(8):2871–81.

    Article  CAS  Google Scholar 

  58. Qiu C, Kivipelto M, von Strauss E. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci. 2009;11(2):111–28.

    Article  Google Scholar 

  59. Breijyeh Z, Karaman R. Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules. 2020. https://doi.org/10.3390/molecules25245789.

    Article  Google Scholar 

  60. Milionis HJ, Florentin M, Giannopoulos S. Metabolic syndrome and Alzheimer’s disease: a link to a vascular hypothesis? CNS Spectr. 2008;13(7):606–13.

    Article  Google Scholar 

  61. Bye CM, McDonald RJ. A specific role of hippocampal NMDA receptors and Arc protein in rapid encoding of novel environmental representations and a more general long-term consolidation function. Front Behav Neurosci. 2019. https://doi.org/10.3389/fnbeh.2019.00008.

    Article  Google Scholar 

  62. Li F, Tsien JZ. Memory and the NMDA receptors. N Engl J Med. 2009;361(3):302.

    Article  CAS  Google Scholar 

  63. Sumi T, Harada K. Mechanism underlying hippocampal long-term potentiation and depression based on competition between endocytosis and exocytosis of AMPA receptors. Sci Rep. 2020;10(1):14711.

    Article  CAS  Google Scholar 

  64. Bliss TVP, Collingridge GL. Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide. Mol Brain. 2013;6(1):5.

    Article  CAS  Google Scholar 

  65. Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013;14(6):383–400.

    Article  CAS  Google Scholar 

  66. Kakizawa S, Yamada K, Iino M, Watanabe M, Kano M. Effects of insulin-like growth factor I on climbing fibre synapse elimination during cerebellar development. Eur J Neurosci. 2003;17(3):545–54.

    Article  Google Scholar 

  67. Ramsey MM, Adams MM, Ariwodola OJ, Sonntag WE, Weiner JL. Functional characterization of des-IGF-1 action at excitatory synapses in the CA1 region of rat hippocampus. J Neurophysiol. 2005;94(1):247–54.

    Article  CAS  Google Scholar 

  68. Xing C, Yin Y, Chang R, Gong X, He X, Xie Z. Effects of insulin-like growth factor 1 on synaptic excitability in cultured rat hippocampal neurons. Exp Neurol. 2007;205(1):222–9.

    Article  CAS  Google Scholar 

  69. Shi L, Linville MC, Tucker EW, Sonntag WE, Brunso-Bechtold JK. Differential effects of aging and insulin-like growth factor-1 on synapses in CA1 of rat hippocampus. Cereb Cortex. 2005;15(5):571–7.

    Article  Google Scholar 

  70. Xing C, Yin Y, Chang R, He X, Xie Z. A role of insulin-like growth factor 1 in beta amyloid-induced disinhibition of hippocampal neurons. Neurosci Lett. 2005;384(1–2):93–7.

    Article  CAS  Google Scholar 

  71. Esteban JA, Shi SH, Wilson C, Nuriya M, Huganir RL, Malinow R. PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nat Neurosci. 2003;6(2):136–43.

    Article  CAS  Google Scholar 

  72. Bredt DS, Nicoll RA. AMPA receptor trafficking at excitatory synapses. Neuron. 2003;40(2):361–79.

    Article  CAS  Google Scholar 

  73. de la Vega AG, Buño W, Pons S, Garcia-Calderat MS, Garcia-Galloway E, Torres-Aleman I. Insulin-like growth factor I potentiates kainate receptors through a phosphatidylinositol 3-kinase dependent pathway. NeuroReport. 2001;12(6):1293–6.

    Article  Google Scholar 

  74. Sanchez JC, Lopez-Zapata DF, Francis L, De Los RL. Effects of estradiol and IGF-1 on the sodium calcium exchanger in rat cultured cortical neurons. Cell Mol Neurobiol. 2011;31(4):619–27.

    Article  CAS  Google Scholar 

  75. Xing C, Yin Y, He X, Xie Z. Effects of insulin-like growth factor 1 on voltage-gated ion channels in cultured rat hippocampal neurons. Brain Res. 2006;1072(1):30–5.

    Article  CAS  Google Scholar 

  76. Evans AJ, Gurung S, Henley JM, Nakamura Y, Wilkinson KA. Exciting times: new advances towards understanding the regulation and roles of kainate receptors. Neurochem Res. 2019;44(3):572–84.

    Article  CAS  Google Scholar 

  77. Isaac JTR, Mellor J, Hurtado D, Roche KW. Kainate receptor trafficking: physiological roles and molecular mechanisms. Pharmacol Ther. 2004;104(3):163–72.

    Article  CAS  Google Scholar 

  78. Darstein M, Petralia RS, Swanson GT, Wenthold RJ, Heinemann SF. Distribution of kainate receptor subunits at hippocampal mossy fiber synapses. J Neurosci. 2003;23(22):8013.

    Article  CAS  Google Scholar 

  79. Fadool DA, Tucker K, Phillips JJ, Simmen JA. Brain insulin receptor causes activity-dependent current suppression in the olfactory bulb through multiple phosphorylation of Kv13. J Neurophysiol. 2000;83(4):2332–48.

    Article  CAS  Google Scholar 

  80. Pekic S, Popovic V. Management of endocrine disease: GH therapy and cancer risk in hypopituitarism: what we know from human studies. Eur J Endocrinol. 2013;169(5):R89–97.

    Article  CAS  Google Scholar 

  81. Hua H, Kong Q, Yin J, Zhang J, Jiang Y. Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy. J Hematol Oncol. 2020;13(1):64.

    Article  Google Scholar 

  82. Westwood AJ, Beiser A, Decarli C, Harris TB, Chen TC, He XM, et al. Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy. Neurology. 2014;82(18):1613–9.

    Article  CAS  Google Scholar 

  83. Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I. Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med. 2002;8(12):1390–7.

    Article  CAS  Google Scholar 

  84. Kimoto A, Kasanuki K, Kumagai R, Shibata N, Ichimiya Y, Arai H. Serum insulin-like growth factor-I and amyloid beta protein in Alzheimer’s disease: relationship with cognitive function. Psychogeriatrics. 2016;16(4):247–54.

    Article  Google Scholar 

  85. Kang K, Bai J, Zhong S, Zhang R, Zhang X, Xu Y, et al. Down-regulation of insulin like growth factor 1 involved in Alzheimer’s disease via MAPK, Ras, and FoxO signaling pathways. Oxid Med Cell Longev. 2022;2022:8169981.

    Article  Google Scholar 

  86. Fukudome Y, Tabata T, Miyoshi T, Haruki S, Araishi K, Sawada S, et al. Insulin-like growth factor-I as a promoting factor for cerebellar Purkinje cell development. Eur J Neurosci. 2003;17(10):2006–16.

    Article  Google Scholar 

  87. Zheng WH, Quirion R. Comparative signaling pathways of insulin-like growth factor-1 and brain-derived neurotrophic factor in hippocampal neurons and the role of the PI3 kinase pathway in cell survival. J Neurochem. 2004;89(4):844–52.

    Article  CAS  Google Scholar 

  88. Zheng WH, Quirion R. Insulin-like growth factor-1 (IGF-1) induces the activation/phosphorylation of Akt kinase and cAMP response element-binding protein (CREB) by activating different signaling pathways in PC12 cells. BMC Neurosci. 2006;7:51.

    Article  Google Scholar 

  89. Ma K, Xu H, Zhang J, Zhao F, Liang H, Sun H, et al. Insulin-like growth factor-1 enhances neuroprotective effects of neural stem cell exosomes after spinal cord injury via an miR-219a-2-3p/YY1 mechanism. Aging. 2019;11(24):12278–94.

    Article  CAS  Google Scholar 

  90. Decourt B, Lahiri DK, Sabbagh MN. Targeting tumor necrosis factor alpha for Alzheimer’s disease. Curr Alzheimer Res. 2017;14(4):412–25.

    Article  CAS  Google Scholar 

  91. Whiten DR, Brownjohn PW, Moore S, De S, Strano A, Zuo Y, et al. Tumour necrosis factor induces increased production of extracellular amyloid-β- and α-synuclein-containing aggregates by human Alzheimer’s disease neurons. Brain Commun. 2020;2(2):fcaa146.

    Article  Google Scholar 

  92. Johanson CE, Johanson NL. Choroid plexus blood-CSF barrier: major player in brain disease modeling and neuromedicine. J Neurol Neuromed. 2018. https://doi.org/10.29245/2572.942X/2018/4.1194.

    Article  Google Scholar 

  93. Johanson C, McMillan P, Tavares R, Spangenberger A, Duncan J, Silverberg G, et al. Homeostatic capabilities of the choroid plexus epithelium in Alzheimer’s disease. Cerebrospinal Fluid Res. 2004;1(1):3.

    Article  Google Scholar 

  94. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013.

    Article  Google Scholar 

  95. Radhakrishnan S, Menon UK, Sundaram KR. Usefulness of a modified questionnaire as a screening tool for swallowing disorders in Parkinson disease: a pilot study. Neurol India. 2019;67(1):118–22.

    Google Scholar 

  96. Nadjar A, Berton O, Guo S, Leneuve P, Dovero S, Diguet E, et al. IGF-1 signaling reduces neuro-inflammatory response and sensitivity of neurons to MPTP. Neurobiol Aging. 2009;30(12):2021–30.

    Article  CAS  Google Scholar 

  97. Bernhard FP, Heinzel S, Binder G, Weber K, Apel A, Roeben B, et al. Insulin-like growth factor 1 (IGF-1) in Parkinson’s disease: potential as trait-, progression- and prediction marker and confounding factors. PLoS ONE. 2016;11(3): e0150552.

    Article  Google Scholar 

  98. Ghazi Sherbaf F, Mohajer B, Ashraf-Ganjouei A, Mojtahed Zadeh M, Javinani A, Sanjari Moghaddam H, et al. Serum insulin-like growth factor-1 in Parkinson’s disease; study of cerebrospinal fluid biomarkers and white matter microstructure. Front Endocrinol. 2018;9:608.

    Article  Google Scholar 

  99. Godau J, Herfurth M, Kattner B, Gasser T, Berg D. Increased serum insulin-like growth factor 1 in early idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2010;81(5):536–8.

    Article  Google Scholar 

  100. Guan J, Krishnamurthi R, Waldvogel HJ, Faull RL, Clark R, Gluckman P. N-terminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats. Brain Res. 2000;859(2):286–92.

    Article  CAS  Google Scholar 

  101. Krishnamurthi R, Stott S, Maingay M, Faull RL, McCarthy D, Gluckman P, et al. N-terminal tripeptide of IGF-1 improves functional deficits after 6-OHDA lesion in rats. NeuroReport. 2004;15(10):1601–4.

    Article  CAS  Google Scholar 

  102. Quesada A, Micevych PE. Estrogen interacts with the IGF-1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6-hydroxdopamine lesions. J Neurosci Res. 2004;75(1):107–16.

    Article  CAS  Google Scholar 

  103. Ebert AD, Beres AJ, Barber AE, Svendsen CN. Human neural progenitor cells over-expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson’s disease. Exp Neurol. 2008;209(1):213–23.

    Article  CAS  Google Scholar 

  104. Pristerà A, Blomeley C, Lopes E, Threlfell S, Merlini E, Burdakov D, et al. Dopamine neuron-derived IGF-1 controls dopamine neuron firing, skill learning, and exploration. Proc Natl Acad Sci USA. 2019;116(9):3817–26.

    Article  Google Scholar 

  105. Quesada A, Lee BY, Micevych PE. PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson’s disease. Dev Neurobiol. 2008;68(5):632–44.

    Article  CAS  Google Scholar 

  106. Wang L, Yang HJ, Xia YY, Feng ZW. Insulin-like growth factor 1 protects human neuroblastoma cells SH-EP1 against MPP+-induced apoptosis by AKT/GSK-3β/JNK signaling. Apoptosis. 2010;15(12):1470–9.

    Article  CAS  Google Scholar 

  107. Alberti KG, Zimmet P, Shaw J. The metabolic syndrome—a new worldwide definition. Lancet. 2005;366(9491):1059–62.

    Article  Google Scholar 

  108. Saklayen MG. The global epidemic of the metabolic syndrome. Curr Hypertens Rep. 2018;20(2):12.

    Article  Google Scholar 

  109. Watts AS, Loskutova N, Burns JM, Johnson DK. Metabolic syndrome and cognitive decline in early Alzheimer’s disease and healthy older adults. J Alzheimer’s Dis. 2013;35(2):253–65.

    Article  CAS  Google Scholar 

  110. Wang F, Zhao M, Han Z, Li D, Zhang S, Zhang Y, et al. Long-term subclinical hyperglycemia and hypoglycemia as independent risk factors for mild cognitive impairment in elderly people. Tohoku J Exp Med. 2017;242(2):121–8.

    Article  CAS  Google Scholar 

  111. Zhong Y, Zhu Y, He T, Li W, Li Q, Miao Y. Brain-derived neurotrophic factor inhibits hyperglycemia-induced apoptosis and downregulation of synaptic plasticity-related proteins in hippocampal neurons via the PI3K/Akt pathway. Int J Mol Med. 2019;43(1):294–304.

    CAS  Google Scholar 

  112. Mukherjee A, Mehta BK, Sen KK, Banerjee S. Metabolic syndrome-associated cognitive decline in mice: role of minocycline. Indian J Pharmacol. 2018;50(2):61–8.

    Article  CAS  Google Scholar 

  113. Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci. 2020. https://doi.org/10.3390/ijms21176275.

    Article  Google Scholar 

  114. Robertson K, Lu Y, De Jesus K, Li B, Su Q, Lund PK, et al. A general and islet cell-enriched overexpression of IGF-I results in normal islet cell growth, hypoglycemia, and significant resistance to experimental diabetes. Am J Physiol Endocrinol Metab. 2008;294(5):E928–38.

    Article  CAS  Google Scholar 

  115. Spauwen PJ, Köhler S, Verhey FR, Stehouwer CD, van Boxtel MP. Effects of type 2 diabetes on 12-year cognitive change: results from the Maastricht aging study. Diabetes Care. 2013;36(6):1554–61.

    Article  Google Scholar 

  116. Li X, Song D, Leng SX. Link between type 2 diabetes and Alzheimer’s disease: from epidemiology to mechanism and treatment. Clin Interv Aging. 2015;10:549–60.

    Article  Google Scholar 

  117. Mittal K, Katare DP. Shared links between type 2 diabetes mellitus and Alzheimer’s disease: a review. Diabetes Metab Syndr. 2016;10(2 Suppl 1):S144–9.

    Article  Google Scholar 

  118. Adzovic L, Lynn AE, D’Angelo HM, Crockett AM, Kaercher RM, Royer SE, et al. Insulin improves memory and reduces chronic neuroinflammation in the hippocampus of young but not aged brains. J Neuroinflammation. 2015;12:63.

    Article  Google Scholar 

  119. Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29(10):1326–34.

    Article  CAS  Google Scholar 

  120. Ortiz GG, Huerta M, Gonzalez-Usigli HA, Torres-Sanchez ED, Delgado-Lara DL, Pacheco-Moises FP, et al. Cognitive disorder and dementia in type 2 diabetes mellitus. World J Diabetes. 2022;13(4):319–37.

    Article  Google Scholar 

  121. Yuan XY, Wang XG. Mild cognitive impairment in type 2 diabetes mellitus and related risk factors: a review. Rev Neurosci. 2017;28(7):715–23.

    Article  Google Scholar 

  122. Rui-Hua C, Yong-de P, Xiao-Zhen J, Chen J, Bin Z. Decreased levels of serum IGF-1 and vitamin D are associated with cognitive impairment in patients with type 2 diabetes. Am J Alzheimers Dis Other Demen. 2019;34(7–8):450–6.

    Article  Google Scholar 

  123. Huang R, Wang P, Han J, Xia W, Cai R, Sun H, et al. Decreased serum IGF-1/IGFBP-3 Molar ratio is associated with executive function behaviors in type 2 diabetic patients with mild cognitive impairment. J Alzheimer’s Dis. 2015;48(3):875.

    Article  Google Scholar 

  124. Aksu I, Ates M, Baykara B, Kiray M, Sisman AR, Buyuk E, et al. Anxiety correlates to decreased blood and prefrontal cortex IGF-1 levels in streptozotocin induced diabetes. Neurosci Lett. 2012;531(2):176–81.

    Article  CAS  Google Scholar 

  125. Jing YH, Song YF, Yao YM, Yin J, Wang DG, Gao LP. Retardation of fetal dendritic development induced by gestational hyperglycemia is associated with brain insulin/IGF-I signals. Int J Dev Neurosci. 2014;37:15–20.

    Article  CAS  Google Scholar 

  126. Srinivasan S, Stevens M, Wiley JW. Diabetic peripheral neuropathy: evidence for apoptosis and associated mitochondrial dysfunction. Diabetes. 2000;49(11):1932–8.

    Article  CAS  Google Scholar 

  127. Vinik AI, Casellini CM. Guidelines in the management of diabetic nerve pain: clinical utility of pregabalin. Diabetes Metab Syndr Obes. 2013;6:57–78.

    Article  CAS  Google Scholar 

  128. Chu Q, Moreland R, Yew NS, Foley J, Ziegler R, Scheule RK. Systemic Insulin-like growth factor-1 reverses hypoalgesia and improves mobility in a mouse model of diabetic peripheral neuropathy. Mol Ther. 2008;16(8):1400–8.

    Article  CAS  Google Scholar 

  129. Russell JW, Cheng H-L, Golovoy D. Insulin-like growth factor-i promotes myelination of peripheral sensory axons. J Neuropathol Exp Neurol. 2000;59(7):575–84.

    Article  CAS  Google Scholar 

  130. Ye P, Li L, Lund PK, D’Ercole AJ. Deficient expression of insulin receptor substrate-1 (IRS-1) fails to block insulin-like growth factor-I (IGF-I) stimulation of brain growth and myelination. Brain Res Dev Brain Res. 2002;136(2):111–21.

    Article  CAS  Google Scholar 

  131. Dávila D, Fernández S, Torres-Alemán I. Astrocyte resilience to oxidative stress induced by insulin-like growth factor I (IGF-I) involves preserved AKT (protein kinase B) activity. J Biol Chem. 2016;291(23):12039.

    Article  Google Scholar 

  132. Genis L, Dávila D, Fernandez S, Pozo-Rodrigálvarez A, Martínez-Murillo R, Torres-Aleman I. Astrocytes require insulin-like growth factor I to protect neurons against oxidative injury. F1000Res. 2014;3:28.

    Article  Google Scholar 

  133. Yu J, Li J, Zhang S, Xu X, Zheng M, Jiang G, et al. IGF-1 induces hypoxia-inducible factor 1α-mediated GLUT3 expression through PI3K/Akt/mTOR dependent pathways in PC12 cells. Brain Res. 2012;1430:18–24.

    Article  CAS  Google Scholar 

  134. Chen X, Le Y, Tang S-Q, He W-y, He J, Wang Y-h, et al. Painful Diabetic Neuropathy Is Associated with Compromised Microglial IGF-1 Signaling Which Can Be Rescued by Green Tea Polyphenol EGCG in Mice. Oxidative medicine and cellular longevity. 2022;2022:6773662.

  135. Ransohoff RM. A polarizing question: do M1 and M2 microglia exist? Nat Neurosci. 2016;19(8):987–91.

    Article  CAS  Google Scholar 

  136. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91(2):461–553.

    Article  CAS  Google Scholar 

  137. Labandeira-Garcia JL, Costa-Besada MA, Labandeira CM, Villar-Cheda B, Rodríguez-Perez AI. Insulin-like growth factor-1 and neuroinflammation. Front Aging Neurosci. 2017. https://doi.org/10.3389/fnagi.2017.00365.

    Article  Google Scholar 

  138. Labandeira-Garcia JL, Rodríguez-Perez AI, Garrido-Gil P, Rodriguez-Pallares J, Lanciego JL, Guerra MJ. Brain renin-angiotensin system and microglial polarization: implications for aging and neurodegeneration. Front Aging Neurosci. 2017. https://doi.org/10.3389/fnagi.2017.0012.

    Article  Google Scholar 

  139. Suh HS, Zhao ML, Derico L, Choi N, Lee SC. Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators. J Neuroinflammation. 2013;10:37.

    Article  CAS  Google Scholar 

  140. Spadaro O, Camell CD, Bosurgi L, Nguyen KY, Youm YH, Rothlin CV, et al. IGF1 shapes macrophage activation in response to immunometabolic challenge. Cell Rep. 2017;19(2):225–34.

    Article  CAS  Google Scholar 

  141. Sun Z, Wu K, Gu L, Huang L, Zhuge Q, Yang S, et al. IGF-1R stimulation alters microglial polarization via TLR4/NF-kappaB pathway after cerebral hemorrhage in mice. Brain Res Bull. 2020;164:221–34.

    Article  CAS  Google Scholar 

  142. Mirdamadi Y, Bommhardt U, Goihl A, Guttek K, Zouboulis CC, Quist S, et al. Insulin and Insulin-like growth factor-1 can activate the phosphoinositide-3-kinase/Akt/FoxO1 pathway in T cells in vitro. Dermatoendocrinol. 2017;9(1): e1356518.

    Article  Google Scholar 

  143. Obadia N, Andrade G, Leardini-Tristao M, Albuquerque L, Garcia C, Lima F, et al. TLR4 mutation protects neurovascular function and cognitive decline in high-fat diet-fed mice. J Neuroinflammation. 2022;19(1):104.

    Article  CAS  Google Scholar 

  144. Bellini MJ, Hereñú CB, Goya RG, Garcia-Segura LM. Insulin-like growth factor-I gene delivery to astrocytes reduces their inflammatory response to lipopolysaccharide. J Neuroinflammation. 2011;8(1):21.

    Article  CAS  Google Scholar 

  145. Wolters TLC, Netea MG, Hermus A, Smit JWA, Netea-Maier RT. IGF1 potentiates the pro-inflammatory response in human peripheral blood mononuclear cells via MAPK. J Mol Endocrinol. 2017;59(2):129–39.

    Article  CAS  Google Scholar 

  146. Lee WJ. IGF-I exerts an anti-inflammatory effect on skeletal muscle cells through down-regulation of TLR4 signaling. Immune Netw. 2011;11(4):223–6.

    Article  Google Scholar 

  147. Finicelli M, Squillaro T, Di Cristo F, Di Salle A, Melone MAB, Galderisi U, et al. Metabolic syndrome, Mediterranean diet, and polyphenols: evidence and perspectives. J Cell Physiol. 2019;234(5):5807–26.

    Article  CAS  Google Scholar 

  148. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384(9945):766–81.

    Article  Google Scholar 

  149. Misra A, Khurana L. Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab. 2008;93(11 Suppl 1):S9-30.

    Article  CAS  Google Scholar 

  150. Deckers K, Van Boxtel MPJ, Verhey FRJ, Köhler S. Obesity and cognitive decline in adults: effect of methodological choices and confounding by age in a longitudinal study. J Nutr Health Aging. 2017;21(5):546–53.

    Article  CAS  Google Scholar 

  151. Ganguli M, Beer JC, Zmuda JM, Ryan CM, Sullivan KJ, Chang CH, et al. Aging, diabetes, obesity, and cognitive decline: a population-based study. J Am Geriatr Soc. 2020;68(5):991–8.

    Article  Google Scholar 

  152. Chen J, Guan Z, Wang L, Song G, Ma B, Wang Y. Meta-analysis: overweight, obesity, and Parkinson’s disease. Int J Endocrinol. 2014;2014: 203930.

    Google Scholar 

  153. Palacios N, Gao X, McCullough ML, Jacobs EJ, Patel AV, Mayo T, et al. Obesity, diabetes, and risk of Parkinson’s disease. Mov Disord. 2011;26(12):2253–9.

    Article  Google Scholar 

  154. Waldstein SR, Katzel LI. Interactive relations of central versus total obesity and blood pressure to cognitive function. Int J Obes. 2006;30(1):201–7.

    Article  CAS  Google Scholar 

  155. Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, et al. Brain dopamine and obesity. Lancet. 2001;357(9253):354–7.

    Article  CAS  Google Scholar 

  156. Bhat NR, Thirumangalakudi L. Increased tau phosphorylation and impaired brain insulin/IGF signaling in mice fed a high fat/high cholesterol diet. J Alzheimer’s Dis. 2013;36(4):781–9.

    Article  CAS  Google Scholar 

  157. Guerra-Cantera S, Frago LM, Jiménez-Hernaiz M, Ros P, Freire-Regatillo A, Barrios V, et al. Impact of long-term HFD intake on the peripheral and central IGF system in male and female mice. Metabolites. 2020;10(11):462.

    Article  CAS  Google Scholar 

  158. Ogundele OM, Pardo J, Francis J, Goya RG, Lee CC. A putative mechanism of age-related synaptic dysfunction based on the impact of IGF-1 receptor signaling on synaptic CaMKIIα phosphorylation. Front Neuroanat. 2018. https://doi.org/10.3389/fnana.2018.00035.

    Article  Google Scholar 

  159. Sun MK, Alkon DL. Links between Alzheimer’s disease and diabetes. Drugs of today. 2006;42(7):481–9.

    Article  CAS  Google Scholar 

  160. Pasinetti GM, Eberstein JA. Metabolic syndrome and the role of dietary lifestyles in Alzheimer’s disease. J Neurochem. 2008;106(4):1503–14.

    Article  CAS  Google Scholar 

  161. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507–20.

    Article  CAS  Google Scholar 

  162. Canavan M, O’Donnell MJ. Hypertension and cognitive impairment: a review of mechanisms and key concepts. Front Neurol. 2022;13: 821135.

    Article  Google Scholar 

  163. Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, et al. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab. 2013;33(11):1732–42.

    Article  CAS  Google Scholar 

  164. Toth P, Tucsek Z, Tarantini S, Sosnowska D, Gautam T, Mitschelen M, et al. IGF-1 deficiency impairs cerebral myogenic autoregulation in hypertensive mice. J Cereb Blood Flow Metab. 2014;34(12):1887–97.

    Article  CAS  Google Scholar 

  165. Ungvari Z, Csiszar A. The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. J Gerontol A Biol Sci Med Sci. 2012;67(6):599–610.

    Article  Google Scholar 

  166. Bailey-Downs LC, Sosnowska D, Toth P, Mitschelen M, Gautam T, Henthorn JC, et al. Growth hormone and IGF-1 deficiency exacerbate high-fat diet-induced endothelial impairment in obese Lewis dwarf rats: implications for vascular aging. J Gerontol A Biol Sci Med Sci. 2012;67(6):553–64.

    Article  Google Scholar 

  167. Riddle DR, Sonntag WE, Lichtenwalner RJ. Microvascular plasticity in aging. Ageing Res Rev. 2003;2(2):149–68.

    Article  Google Scholar 

  168. Csiszar A, Labinskyy N, Perez V, Recchia FA, Podlutsky A, Mukhopadhyay P, et al. Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice. Am J Physiol Heart Circ Physiol. 2008;295(5):H1882–94.

    Article  CAS  Google Scholar 

  169. Toth P, Tarantini S, Ashpole NM, Tucsek Z, Milne GL, Valcarcel-Ares NM, et al. IGF-1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging. Aging Cell. 2015;14(6):1034–44.

    Article  CAS  Google Scholar 

  170. Kubik LL, Philbert MA. The role of astrocyte mitochondria in differential regional susceptibility to environmental neurotoxicants: tools for understanding neurodegeneration. Toxicol Sci. 2015;144(1):7–16.

    Article  CAS  Google Scholar 

  171. Parihar MS, Kunz EA, Brewer GJ. Age-related decreases in NAD(P)H and glutathione cause redox declines before ATP loss during glutamate treatment of hippocampal neurons. J Neurosci Res. 2008;86(10):2339–52.

    Article  CAS  Google Scholar 

  172. Parihar MS, Brewer GJ. Mitoenergetic failure in Alzheimer disease. Am J Physiol Cell Physiol. 2007;292(1):C8-23.

    Article  CAS  Google Scholar 

  173. Vančová O, Bačiak L, Kašparová S, Kucharská J, Palacios HH, Horecký J, et al. In vivo and in vitro assessment of brain bioenergetics in aging rats. J Cell Mol Med. 2010;14(11):2667–74.

    Article  Google Scholar 

  174. Elfawy HA, Das B. Crosstalk between mitochondrial dysfunction, oxidative stress, and age related neurodegenerative disease: etiologies and therapeutic strategies. Life Sci. 2019;218:165–84.

    Article  CAS  Google Scholar 

  175. Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013;8(21):2003–14.

    CAS  Google Scholar 

  176. Islam MT. Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurol Res. 2017;39(1):73–82.

    Article  CAS  Google Scholar 

  177. Bartke A, List EO, Kopchick JJ. The somatotropic axis and aging: benefits of endocrine defects. Growth Horm IGF Res. 2016;27:41–5.

    Article  CAS  Google Scholar 

  178. Ge L, Liu S, Rubin L, Lazarovici P, Zheng W. Research progress on neuroprotection of insulin-like growth factor-1 towards glutamate-induced neurotoxicity. Cells. 2022. https://doi.org/10.3390/cells11040666.

    Article  Google Scholar 

  179. Redmond L, Kashani AH, Ghosh A. Calcium regulation of dendritic growth via CaM kinase IV and CREB-mediated transcription. Neuron. 2002;34(6):999–1010.

    Article  CAS  Google Scholar 

  180. Yamamoto K, Sakagami Y, Sugiura S, Inokuchi K, Shimohama S, Kato N. Homer 1a enhances spike-induced calcium influx via L-type calcium channels in neocortex pyramidal cells. Eur J Neurosci. 2005;22(6):1338–48.

    Article  Google Scholar 

  181. Gao L, Blair LAC, Salinas GD, Needleman LA, Marshall J. Insulin-like growth factor-1 modulation of CaV1.3 calcium channels depends on Ca2+ release from IP3-sensitive stores and calcium/calmodulin kinase II phosphorylation of the alpha1 subunit EF hand. J Neurosci. 2006;26(23):6259–68.

    Article  CAS  Google Scholar 

  182. Marshall J, Dolan BM, Garcia EP, Sathe S, Tang X, Mao Z, et al. Calcium channel and NMDA receptor activities differentially regulate nuclear C/EBPbeta levels to control neuronal survival. Neuron. 2003;39(4):625–39.

    Article  CAS  Google Scholar 

  183. Yang C, Sui G, Li D, Wang L, Zhang S, Lei P, et al. Exogenous IGF-1 alleviates depression-like behavior and hippocampal mitochondrial dysfunction in high-fat diet mice. Physiol Behav. 2021;229: 113236.

    Article  CAS  Google Scholar 

  184. Backeljauw PF, Underwood LE. Therapy for 6.5–7.5 years with recombinant insulin-like growth factor I in children with growth hormone insensitivity syndrome: a clinical research center study. J Clin Endocrinol Metab. 2001;86(4):1504–10.

    CAS  Google Scholar 

  185. Torres-Aleman I. Toward a comprehensive neurobiology of IGF-I. Dev Neurobiol. 2010;70(5):384–96.

    CAS  Google Scholar 

  186. ter Braak B, Siezen C, Speksnijder EN, Koedoot E, van Steeg H, Salvatori DC, et al. Mammary gland tumor promotion by chronic administration of IGF1 and the insulin analogue AspB10 in the p53R270H/(+)WAPCre mouse model. Breast Cancer Res. 2015;17:14.

    Article  Google Scholar 

  187. Heskamp S, Boerman OC, Molkenboer-Kuenen JD, Wauters CA, Strobbe LJ, Mandigers CM, et al. Upregulation of IGF-1R expression during neoadjuvant therapy predicts poor outcome in breast cancer patients. PLoS ONE. 2015;10(2): e0117745.

    Article  Google Scholar 

  188. Hayes CA, Valcarcel-Ares MN, Ashpole NM. Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke. J Cereb Blood Flow Metab. 2021;41(10):2475–91.

    Article  CAS  Google Scholar 

  189. Tarantini S, Nyúl-Tóth Á, Yabluchanskiy A, Csipo T, Mukli P, Balasubramanian P, et al. Endothelial deficiency of insulin-like growth factor-1 receptor (IGF1R) impairs neurovascular coupling responses in mice, mimicking aspects of the brain aging phenotype. GeroScience. 2021;43(5):2387–94.

    Article  CAS  Google Scholar 

  190. Horvath A, Salman Z, Quinlan P, Wallin A, Svensson J. Patients with Alzheimer’s disease have increased levels of insulin-like growth factor-i in serum but not in cerebrospinal fluid. J Alzheimer’s Dis. 2020;75(1):289–98.

    Article  CAS  Google Scholar 

  191. Pharaoh G, Owen D, Yeganeh A, Premkumar P, Farley J, Bhaskaran S, et al. Disparate central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function. Mol Neurobiol. 2020;57(3):1317–31.

    Article  CAS  Google Scholar 

  192. Prabhu D, Khan SM, Blackburn K, Marshall JP, Ashpole NM. Loss of insulin-like growth factor-1 signaling in astrocytes disrupts glutamate handling. J Neurochem. 2019;151(6):689–702.

    Article  CAS  Google Scholar 

  193. Logan S, Pharaoh GA, Marlin MC, Masser DR, Matsuzaki S, Wronowski B, et al. Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes. Mol Metab. 2018;9:141–55.

    Article  CAS  Google Scholar 

  194. Nageeb RS, Hashim NA, Fawzy A. Serum insulin-like growth factor 1 (IGF-1) in multiple sclerosis: relation to cognitive impairment and fatigue. Egypt J Neurol Psychiatry Neurosurg. 2018;54(1):25.

    Article  Google Scholar 

  195. Quinlan P, Horvath A, Nordlund A, Wallin A, Svensson J. Low serum insulin-like growth factor-I (IGF-I) level is associated with increased risk of vascular dementia. Psychoneuroendocrinology. 2017;86:169–75.

    Article  CAS  Google Scholar 

  196. Vidal JS, Hanon O, Funalot B, Brunel N, Viollet C, Rigaud AS, et al. Low serum insulin-like growth factor-i predicts cognitive decline in Alzheimer’s disease. J Alzheimer’s Dis. 2016;52(2):641–9.

    Article  CAS  Google Scholar 

  197. Hu X, Yang Y, Gong D. Circulating insulin-like growth factor 1 and insulin-like growth factor binding protein-3 level in Alzheimer’s disease: a meta-analysis. Neurol Sci. 2016;37(10):1671–7.

    Article  Google Scholar 

  198. Nieto-Estevez V, Oueslati-Morales CO, Li L, Pickel J, Morales AV, Vicario-Abejon C. Brain insulin-like growth factor-i directs the transition from stem cells to mature neurons during postnatal/adult hippocampal neurogenesis. Stem Cells. 2016;34(8):2194–209.

    Article  CAS  Google Scholar 

  199. Basta-Kaim A, Szczesny E, Glombik K, Stachowicz K, Slusarczyk J, Nalepa I, et al. Prenatal stress affects insulin-like growth factor-1 (IGF-1) level and IGF-1 receptor phosphorylation in the brain of adult rats. Eur Neuropsychopharmacol. 2014;24(9):1546–56.

    Article  CAS  Google Scholar 

  200. Johansson P, Åberg D, Johansson J-O, Mattsson N, Hansson O, Ahrén B, et al. Serum but not cerebrospinal fluid levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) are increased in Alzheimer’s disease. Psychoneuroendocrinology. 2013;38(9):1729–37.

    Article  CAS  Google Scholar 

  201. Duron E, Funalot B, Brunel N, Coste J, Quinquis L, Viollet C, et al. Insulin-like growth factor-I and insulin-like growth factor binding protein-3 in Alzheimer’s disease. J Clin Endocrinol Metab. 2012;97(12):4673–81.

    Article  CAS  Google Scholar 

  202. Mitschelen M, Yan H, Farley JA, Warrington JP, Han S, Hereñú CB, et al. Long-term deficiency of circulating and hippocampal insulin-like growth factor I induces depressive behavior in adult mice: a potential model of geriatric depression. Neuroscience. 2011;185:50–60.

    Article  CAS  Google Scholar 

  203. Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010;31(2):224–43.

    Article  CAS  Google Scholar 

  204. Freude S, Hettich MM, Schumann C, Stöhr O, Koch L, Köhler C, et al. Neuronal IGF-1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer’s disease. FASEB J. 2009;23(10):3315–24.

    Article  CAS  Google Scholar 

  205. Watanabe T, Miyazaki A, Katagiri T, Yamamoto H, Idei T, Iguchi T. Relationship between serum insulin-like growth factor-1 levels and Alzheimer’s disease and vascular dementia. J Am Geriatr Soc. 2005;53(10):1748–53.

    Article  Google Scholar 

  206. Selles MC, Fortuna JTS, Zappa-Villar MF, de Faria YPR, Souza AS, Suemoto CK, et al. Adenovirus-mediated transduction of insulin-like growth factor 1 protects hippocampal neurons from the toxicity of abeta oligomers and prevents memory loss in an Alzheimer mouse model. Mol Neurobiol. 2020;57(3):1473–83.

    Article  CAS  Google Scholar 

  207. Farias Quipildor GE, Mao K, Hu Z, Novaj A, Cui M-H, Gulinello M, et al. Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice. GeroScience. 2019;41(2):185–208.

    Article  Google Scholar 

  208. Carlson SW, Saatman KE. Central infusion of insulin-like growth factor-1 increases hippocampal neurogenesis and improves neurobehavioral function after traumatic brain injury. J Neurotrauma. 2018;35(13):1467–80.

    Article  Google Scholar 

  209. Morel GR, Leon ML, Uriarte M, Reggiani PC, Goya RG. Therapeutic potential of IGF-I on hippocampal neurogenesis and function during aging. Neurogenesis. 2017;4(1): e1259709.

    Article  Google Scholar 

  210. Pardo J, Uriarte M, Cónsole GM, Reggiani PC, Outeiro TF, Morel GR, et al. Insulin-like growth factor-I gene therapy increases hippocampal neurogenesis, astrocyte branching and improves spatial memory in female aging rats. Eur J Neurosci. 2016;44(4):2120–8.

    Article  Google Scholar 

  211. Bake S, Selvamani A, Cherry J, Sohrabji F. Blood brain barrier and neuroinflammation are critical targets of IGF-1-mediated neuroprotection in stroke for middle-aged female rats. PLoS ONE. 2014;9(3):e91427.

    Article  Google Scholar 

  212. Jacobsen KT, Adlerz L, Multhaup G, Iverfeldt K. Insulin-like growth factor-1 (IGF-1)-induced Processing of amyloid-β precursor protein (APP) and APP-like protein 2 is mediated by different metalloproteinases. J Biol Chem. 2010;285(14):10223–31.

    Article  CAS  Google Scholar 

  213. Sun X, Huang L, Zhang M, Sun S, Wu Y. Insulin like growth factor-1 prevents 1-mentyl-4-phenylphyridinium-induced apoptosis in PC12 cells through activation of glycogen synthase kinase-3beta. Toxicology. 2010;271(1–2):5–12.

    Article  CAS  Google Scholar 

  214. Kao S-Y. Rescue of α-synuclein cytotoxicity by insulin-like growth factors. Biochem Biophys Res Commun. 2009;385(3):434–8.

    Article  CAS  Google Scholar 

  215. Aghanoori M-R, Smith DR, Shariati-Ievari S, Ajisebutu A, Nguyen A, Desmond F, et al. Insulin-like growth factor-1 activates AMPK to augment mitochondrial function and correct neuronal metabolism in sensory neurons in type 1 diabetes. Mol Metab. 2019;20:149–65.

    Article  CAS  Google Scholar 

  216. Rizk NN, Myatt-Jones J, Rafols J, Dunbar JC. Insulin like growth factor-1 (IGF-1) decreases ischemia-reperfusion induced apoptosis and necrosis in diabetic rats. Endocrine. 2007;31(1):66–71.

    Article  CAS  Google Scholar 

  217. Wold LE, Muralikrishnan D, Albano CB, Norby FL, Ebadi M, Ren J. Insulin-like growth factor I (IGF-1) supplementation prevents diabetes-induced alterations in coenzymes Q9 and Q10. Acta Diabetol. 2003;40(2):85–90.

    Article  CAS  Google Scholar 

  218. Delaney CL, Russell JW, Cheng HL, Feldman EL. Insulin-like growth factor-I and over-expression of Bcl-xL prevent glucose-mediated apoptosis in Schwann cells. J Neuropathol Exp Neurol. 2001;60(2):147–60.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank BioRender.com for creating figures.

Funding

This study was supported by Grant 2022R1A2C1006125 (Juhyun Song) from the National Research Foundation of Korea (NRF), Republic of Korea. HCRI 22019 from the Chonnam National University Hwasun Hospital Institute for Biomedical Science, Korea (Juhyun Song). The authors acknowledged Biorender.com in creating the figures.

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Authors and Affiliations

  1. Department of Anatomy, Chonnam National University Medical School, Hwasun, Jeollanam-Do, 58128, Republic of Korea

    Archana Arjunan & Juhyun Song

  2. Department of Biochemistry, Chonnam National University Medical School, Hwasun, 58128, Republic of Korea

    Dhiraj Kumar Sah

  3. BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 Seoyangro, Hwasun, 58128, Republic of Korea

    Dhiraj Kumar Sah & Juhyun Song

  4. Division of Endocrinology and Metabolism, University Health Network and and Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada

    Minna Woo

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  1. Archana Arjunan
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Writing, AA and JS; Figure, DKS; Manuscript revision, AA and JS; Manuscript finalization, MW and JS. All authors read and approved the final manuscript.

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Correspondence to Juhyun Song.

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Arjunan, A., Sah, D.K., Woo, M. et al. Identification of the molecular mechanism of insulin-like growth factor-1 (IGF-1): a promising therapeutic target for neurodegenerative diseases associated with metabolic syndrome. Cell Biosci 13, 16 (2023). https://doi.org/10.1186/s13578-023-00966-z

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  • DOI: https://doi.org/10.1186/s13578-023-00966-z

Keywords

  • Alzheimer’s disease (AD)
  • Insulin-like growth factor-1 (IGF-1)
  • Metabolic syndrome (MetS)
  • Neurodegeneration
  • Neuroprotection

Cell & Bioscience

ISSN: 2045-3701

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