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

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.

Keywords: Alzheimer’s disease (AD); Insulin-like growth factor-1 (IGF-1); Metabolic syndrome (MetS); Neurodegeneration; Neuroprotection.

Fig. 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)

Fig. 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