Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review

Insulin plays a major neuroprotective and trophic function for cerebral cells population, thus countering apoptosis, beta amyloid toxicity, oxidative stress; favoring neuronal survival, and enhancing memory and learning processes. Insulin resistance and impaired cerebral glucose metabolism are invariantly reported in Alzheimer’s disease (AD) and other neurodegenerative processes. AD is a fatal neurodegenerative disorder in which progressive glucose hypometabolism parallels to cognitive impairment. Although AD may appear and progress in virtue of multifactorial nosogenic ingredients, multiple interperpetuative and interconnected vicious circles appear to drive disease pathophysiology. The disease is primarily a metabolic/energetic disorder in which amyloid accumulation may appear as a by-product of more proximal events. As a bridge between AD and type-2 diabetes, activation of c-Jun N-terminal kinase (JNK) pathway with the ensued serine phosphorylation of the IRS-1/2 may be at the crossroads of insulin resistance and its subsequent dysmetabolic consequences. Central insulin axis bankruptcy translates in neuronal vulnerability and demise. As a link in the chain of pathogenic vicious circles, mitochondrial dysfunction, oxidative stress, and peripheral/central immune-inflammation are increasingly advocated as major pathology drivers. Pharmacological interventions addressed to preserve mitochondrial biogenesis, integral functionality and mitophagy of diseased organelles may attenuate the adjacent spillover of free radicals that further perpetuate mitochondrial damages and catalyzes inflammation. Central and / or peripheral inflammation may account for a local flood of pro-inflammatory cytokines that along with astroglyosis amplifies insulin resistance, mitochondrial dysfunction, and oxidative stress. All these elements are endogenous stressor factors that contribute to JNK activation. Taken together, these evidences incite to identify novel multi-mechanistic approaches to succeed in ameliorating this pandemic affliction.