A fluid connection: Cholesterol and Aβ

Publisher Website
Google Scholar
Abstract
Alzheimer's disease (AD) has long been in the public eye because of its prevalence in the geriatric population, and the fear that the cognitive haze of dementia will strike us. The pathophysiology of AD is thought to derive from a small peptide, termed Aβ, which accumulates in the brain causing neurotoxicity and neurodegeneration. There is accumulating evidence pointing toward a potentially important link between cholesterol, Aβ, and AD. Recent epidemiological studies indicate that the prevalence of AD is reduced among people taking a class of cholesterol lowering medicines, termed HMG-CoA reductase inhibitors (also known as statins), such as simvastatin and lovastatin (1, 2). This work is supported by studies in transgenic mice overexpressing amyloid precursor protein (APP), which is the precursor to Aβ (Fig. 1A). These studies show that cholesterol levels inversely regulate Aβ production and Alzheimer pathology (3). Transgenic APP mice fed high cholesterol diets have more neuritic plaques and higher levels of insoluble Aβ, which is the main component of neuritic plaques. Now, two articles in the current issue of PNAS (4, 5) provide data suggesting how cholesterol might modulate Alzheimer pathology. Both papers study the affects of cholesterol reduction on APP processing and Aβ production. Fassbender et al. (5) use both cell culture and in vivo studies to show that inhibiting cholesterol production reduces Aβ production, and Kojro et al. (4) provide corroborative evidence by showing that inhibiting cholesterol production increases trafficking of APP through the non-amyloidogenic APPsα pathway. Together these papers suggest that inhibiting cholesterol production in the brain might inhibit Aβ production, and reduce the accumulation of Aβ that causes AD. A putative model of the processing of APP in relation to the lipid composition of membranes. (A) APP is a transmembrane protein. (B) Cleavage of APP by α secretases, such as …