Role of cholesterol in APP metabolism and its significance in Alzheimer's disease pathogenesis.

ABSTRACT

Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disorder believed to be initiated by accumulation of amyloid ß (Aß)-related peptides derived from proteolytic processing of amyloid precursor protein (APP). Research over the past two decades provided a mechanistic link between cholesterol and AD pathogenesis. Genetic polymorphisms in genes regulating the pivotal points in cholesterol metabolism have been suggested to enhance the risk of developing AD. Altered neuronal membrane cholesterol level and/or subcellular distribution have been implicated in aberrant formation, aggregation, toxicity, and degradation of Aß-related peptides. However, the results are somewhat contradictory and we still do not have a complete understanding on how cholesterol can influence AD pathogenesis. In this review, we summarize our current understanding on the role of cholesterol in regulating the production/function of Aß-related peptides and also examine the therapeutic potential of regulating cholesterol homeostasis in the treatment of AD pathology.