Insulin resistance in Alzheimer's disease: signalling mechanisms and therapeutics strategies.

Abstract

Background: Alzheimer's disease (AD), one of the most common neurodegenerative disorders, is characterised by hallmark abnormalities such as amyloid-β plaques and neurofibrillary tangles (NFTs). Emerging evidence suggests that faulty insulin signalling contributes to these pathological features, impairing critical cellular and metabolic processes.

Objective: This review aims to elucidate the role of insulin signalling in the central nervous system (CNS) under normal and pathological conditions and to explore therapeutic approaches targeting insulin pathways in AD and other neurodegenerative diseases.

Methods: We reviewed studies highlighting the involvement of insulin-signalling pathways in neuronal health, with a particular focus on the key components-IRS, PI3K, Akt, and GSK-3β-predominantly expressed in cortical and hippocampal regions.

Results: Insulin, an essential growth factor, regulates numerous cellular functions, including glucose metabolism, mitochondrial activity, oxidative stress response, autophagy, synaptic plasticity, and cognitive processes. Altered phosphorylation of signalling molecules in insulin pathways contributes to oxidative stress, inflammation, and the formation of AD hallmarks. Indirect modulators such as NF-κB and caspases further exacerbate neuronal damage, linking impaired insulin signalling to neurodegeneration.

Conclusion: Insulin signalling plays a crucial role in maintaining neuronal health and mitigating neurodegenerative processes. Targeting insulin pathways and associated molecules offers promising therapeutic avenues for AD and other neurodegenerative disorders.