Role of Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

Cognitive dysfunction is the most distinctive symptom of several neurodegenerative disorders like Alzheimer's disease (AD), Multiple sclerosis, Huntington disease (HD) and Parkinson's disease (advanced stage). AD has been categories into two groups, based on onset, the first type is familial AD linked with genetic mutation of the amyloid-beta precursor protein (Amyloid Beta PP) and presenilins (PS1) Another group is the late-onset form (LOAD), also recognized as sporadic which is majority prevalent accounts for 97% of total diagnose Pathologically, AD includes selective pyramidal neuronal death and an accumulation of Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder demonstrated by brain deposition of A, which is responsible for the formation of senile plaques, neurofibrillary tangles (NFT) lead to neurodegeneration and cognitive alteration. Recently, it would be highlighted that alteration in insulin signaling pathways and glucose metabolism, in central along with peripheral systems, could be one of the prime reasons for the cognitive loss. Insulin resistance in the brain, also recognized as Type 3 diabetes, which further increases A production and TAU phosphorylation, protein misfolding, mitochondrial dysfunction, oxidative stress, and cognitive impairment, which are all hallmarks of AD. Evidences indicated that A42 accumulation in the brain would induce hypothalamic dysfunction that leads to peripheral hyperglycemia due to downstream regulation of the insulin receptor in the liver. This review aim is to confer the existing facts which favor the concept that brain insulin resistance and altered glucose metabolism play an important role in the pathology of AD. Furthermore, we discuss AD treatment approaches along with the novel strategy of treating Alzheimer's and with drugs that initially have been developed to treat type 2 diabetes and mTOR inhibitors. As insulin signaling has been interrupted in the brains of AD patient, drugs that can resensitize insulin signaling have been studied to evaluate if this approach can alter disease prognosis.