Glucocorticoids may initiate Alzheimer's disease: a potential therapeutic role for mifepristone (RU-486)

Abstract

Alzheimer's disease (AD) is a relentless neurodegenerative disease of uncertain etiology affecting millions worldwide. Stress is an important etiological factor associated with AD. Stress and glucocorticoids (GCs) are intimately related; so much so that stress is considered to be "a condition that is able to liberate GCs". Normally, GCs are required for various bodily functions but their excess is deleterious. Hippocampus has highest density of GC receptors in brain, is particularly vulnerable to their damaging effects and undergoes reversible atrophy under their influence. Hippocampal atrophy is an initial event for the development of AD, the most common form of dementia. Apart from atrophy, GCs are able to produce a variety of other initial structural and functional changes in hippocampus. For example, these down regulate GC receptors, leading to disruption in negative feedback loop, alter dendtritic morphology and impair axonal transport. Impaired axon transport is probably an initial event that leads to the formation of paired helical filaments. Additionally, they inhibit insulin-degrading enzyme, which degrades A-beta; consequently reducing its clearance. Since GCs mediate a number of initial events in AD pathogenesis, therefore GC antagonists (e.g. mifepristone) can be tried. Mifepristone has intrinsic neuroprotective and antioxidant potential which could offer additional benefits as well. Use of this drug therefore, in those with mild AD or with milder cognitive impairment can be useful. Appropriate dose, duration, safety and efficacy need to be worked out.