The multiple roles of chronic stress and glucocorticoids in Alzheimer's disease pathogenesis

Chronic stress and the accompanying long-term elevation of glucocorticoids (GCs), the stress hormones of the body, increase the risk and accelerate the progression of Alzheimer's disease (AD). Signatures of AD include intracellular tau (MAPT) tangles, extracellular amyloid β (Aβ) plaques, and neuroinflammation. A growing body of work indicates that stress and GCs initiate cellular processes underlying these pathologies through dysregulation of protein homeostasis and trafficking, mitochondrial bioenergetics, and response to damage-associated stimuli. In this review, we integrate findings from mechanistic studies in rodent and cellular models, wherein defined chronic stress protocols or GC administration have been shown to elicit AD-related pathology. We specifically discuss the effects of chronic stress and GCs on tau pathogenesis, including hyperphosphorylation, aggregation, and spreading, amyloid precursor protein (APP) processing and trafficking culminating in Aβ production, immune priming by proinflammatory cytokines and disease-associated molecular patterns, and alterations to glial cell and blood-brain barrier (BBB) function.