Role of insulin receptor substance-1 modulating PI3K/Akt insulin signaling pathway in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease, also regarded as "type 3 diabetes" for the last few years because of the brain insulin resistance (IR) and dysregulation of insulin signaling in the brain, which can further promote pathological progression of AD. IRS-1/PI3K/Akt insulin signaling pathway disorder and its downstream cascade reaction are responsible for cognitive decline in the brain. In recent years, a growing number of studies has documented that dysregulation of insulin signaling is a key feature of AD and has crucial correlations with serine/tyrosine (Ser/Tyr) phosphorylation of insulin receptor substance-1(IRS-1). Phosphorylation of this protein has been identified as an important molecule involved in the process of amyloid-β (Aβ) deposition into senile plaques (SPs) and tau hyperphosphorylation into neurofibrillary tangles (NFTs). In this paper, we review the links between IRS-1 and the PI3K/Akt insulin signaling pathway, and highlight phosphorylated IRS-1 which negatively regulated by downstream effector of Akt such as mTOR, S6K, and JNK, among others in AD. Furthermore, anti-diabetic drugs including metformin, thiazolidinediones, and glucagon-like peptide-1 (GLP-1) analogue could modulate IRS-1 phosphorylation, brain IR, PI3K/Akt insulin signaling pathway, and other pathologic processes of AD. The above suggest that anti-diabetic drugs may be promising strategies for AD disease-modifying treatments.