Cholesterol in Alzheimer's disease and tauopathy.

Cholesterol has been implicated in the pathogenesis of amyloid plaques in Alzheimer's disease (AD) and in the formation of neurofibrillary pathology in Niemann-Pick disease. Several epidemiology studies have implicated high cholesterol as a risk factor for AD and have shown that the use of cholesterol-reducing agents (statins) can be protective against the disease. We and others have shown that cholesterol levels modulate the processing of the amyloid precursor protein (APP) both in vivo and in vitro, affecting the accumulation of A-beta (Abeta) peptides that may directly impact the risk of AD. Mutations in the Niemann-Pick C gene (NPC) result in deficient cholesterol transport/storage. Clinically, Niemann-Pick disease causes a severe childhood lipidosis, with neurodegeneration characterized by the presence of AD-type neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Studies of mouse models of NPC show that defects in cellular cholesterol trafficking are associated with enhanced generation of Abeta and the hyperphosphorylation of tau, further implicating the cholesterol homeostasis pathway as a risk factor for amyloidosis.