Insulin-Like Growth Factor Signaling in Alzheimer's Disease: Pathophysiology and Therapeutic Strategies

Abstract

Alzheimer's disease (AD) is the leading cause of dementia among the elderly population, posing a significant public health challenge due to limited therapeutic options that merely delay cognitive decline. AD is associated with impaired energy metabolism and reduced neurotrophic signaling. The insulin-like growth factor (IGF) signaling pathway, crucial for central nervous system (CNS) development, metabolism, repair, cognition, and emotion regulation, includes IGF-1, IGF-2, IGF-1R, IGF-2R, insulin receptor (IR), and six insulin-like growth factor binding proteins (IGFBPs). Research has identified abnormalities in IGF signaling in individuals with AD and AD models. Dysregulated expression of IGFs, receptors, IGFBPs, and disruptions in downstream phosphoinositide 3-kinase-protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways collectively increase AD susceptibility. Studies suggest modulating the IGF pathway may ameliorate AD pathology and cognitive decline. This review explores the CNS pathophysiology of IGF signaling in AD progression and assesses the potential of targeting the IGF system as a novel therapeutic strategy. Further research is essential to elucidate how aberrant IGF signaling contributes to AD development, understand underlying molecular mechanisms, and evaluate the safety and efficacy of IGF-based treatments.

Keywords: Alzheimer’s disease; Central nervous system; Insulin-like growth factor binding proteins; Insulin-like growth factor receptors; Insulin-like growth factors; Treatment.

Fig. 1

The IGF signaling pathway. IGF-1 and IGF-2 activate IGF signaling pathways by interacting with IGF-1R, IR, and hybrid receptors of IR/IGF-1R (Hybrid-Rs) with different binding affinities. IGF-1R, IR, and Hybrid-Rs consist of two extracellular α-subunits and two transmembrane β-subunits, the tyrosine kinase domain of which self-phosphorylates and phosphorylates insulin receptor substrate 1/2 (IRS-1/2) and Src homology/collagen (SHC) when bound by IGF-1/2. IRS-1/2 further activates the phosphoinositide 3-kinase-protein kinase B (PI3K/AKT) signaling pathway, which regulates numerous downstream signaling molecules and promotes cell growth, proliferation, protein synthesis, and survival. SHC further activates mitogen-activated protein kinase (MAPK) signaling pathways, such as the RAS/RAF/MEK/ERK signaling pathway, to control mitosis and promote cell growth, proliferation, differentiation, repair, and maintenance. IGF-2R/mannose-6-phosphate receptor (M6PR) is a single transmembrane protein receptor. IGF-2R/M6PR exhibits strong attraction to IGF-2 and minimal attraction to IGF-1. The prominent role of IGF-2R/M6PR is to target proteolytic degradation in lysosomes and participate in lysosomal transport. The thickness of the blue arrow represents the affinity between IGF receptors and ligands. IGFBP 1–6 has a high affinity for IGF-1 and IGF-2, which regulate the biological role of IGFs. This figure was created using FigDraw

Fig. 2

IGF signaling in Alzheimer’s disease (AD). The irregularity in the signaling pathways of IGF is noticeable in the pathophysiology of AD. Specifically, the findings indicate a reduction in the expression levels of IGF-1, IGF-2, IGF-1R, insulin receptor substrate 1/2 (IRS-1/2), and the phosphoinositide 3-kinase-protein kinase B (PI3K/AKT) signaling and an elevation in IGFBP-1–6 to varying extents. Downstream effects include the decreased mammalian target of rapamycin (mTOR), B cell lymphoma 2 (Bcl-2), and Bcl-2-associated death promoter (Bad) levels, as well as increased levels of glycogen synthase kinase 3β (GSK-3β) and forkhead box protein O (FOXO). These alterations further contribute to the upregulation of amyloid precursor protein (APP), beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), and γ-secretase, resulting in elevated levels of soluble amyloid precursor protein-β (sAPPβ), β C-terminal fragments (β-CTF), amyloid precursor protein intracellular domain (AICD), and amyloid-β (Aβ), ultimately leading to the formation of Aβ plaques, neurofibrillary tangles, increased neuronal apoptosis, and impaired neuronal survival and growth. This figure was created using FigDraw

Fig. 3

The roles of IGF-1 signaling on AD. APP, amyloid precursor protein; Aβ, amyloid-β. The figure was created using FigDraw