Brain insulin resistance linked Alzheimer’s and Parkinson’s disease pathology: An undying implication of epigenetic and autophagy modulation

In metabolic syndrome, dysregulated signalling activity of the insulin receptor pathway in the brain due to persistent insulin resistance (IR) condition in the periphery may lead to brain IR (BIR) development. BIR causes an upsurge in the activity of glycogen synthase kinase-3 beta, increased amyloid beta (Aβ) accumulation, hyperphosphorylation of tau, aggravated formation of Aβ oligomers and simultaneously neurofibrillary tangle formation, all of which are believed to be direct contributors in Alzheimer’s Disease (AD) pathology. Likewise, for Parkinson’s Disease (PD), BIR is associated with alpha-synuclein alterations, dopamine loss in brain areas which ultimately succumbs towards the appearance of classical motor symptoms corresponding to the typical PD phenotype. Modulation of the autophagy process for clearing misfolded proteins and alteration in histone proteins to alleviate disease progression in BIR-linked AD and PD have recently evolved as a research hotspot, as the majority of the autophagy-related proteins are believed to be regulated by histone posttranslational modifications. Hence, this review will provide a timely update on the possible mechanism(s) converging towards BIR induce AD and PD. Further, emphasis on the potential epigenetic regulation of autophagy that can be effectively targeted for devising a complete therapeutic cure for BIR-induced AD and PD will also be reviewed. Graphical abstract: [Figure not available: see fulltext.]