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 A, which accumulates in the brain causing neurotoxicity and neurodegeneration. There is accumulating evidence pointing toward a potentially important link between cholesterol, A, 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 A (Fig. 1A). These studies show that cholesterol levels inversely regulate A production and Alzheimer pathology (3). Transgenic APP mice fed high cholesterol diets have more neuritic plaques and higher levels of insoluble A, 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 A production. Fassbender et al.(5) use both cell culture and in vivo studies to show that inhibiting cholesterol production reduces A production, and Kojro et al.(4) provide corroborative evidence by showing that inhibiting cholesterol production increases trafficking of APP through the nonamyloidogenic APPs pathway. Together these papers suggest that inhibiting cholesterol production in the brain might inhibit A production, and reduce the accumulation of A that causes AD. To understand how and why cholesterol might impact A production, we need to take a step back and understand the mechanisms of A production. A is made in the endoplasmic reticulum as a result cleavage of APP by particular proteases, termed secretases. Cleavage of APP occurs via two paths (Fig. 1). Most APP is cut at the-secretase site to produce two products, APPs and a C-terminal fragment (Fig. 1B). The APPs protein is a neurotrophic protein that is secreted, whereas the C-terminal fragment is internalized and degraded. Cleavage of APP by-secretase cuts A in half and precludes A production. A small percentage of APP is cleaved by two enzymes, termed and secretases, that lead to production of A (Fig. 1C). Although A is processed from only a small percentage of APP, the pathway producing A is very important because it is responsible for the pathophysiology of AD.

The identity of the enzymes that cleave APP has been the subject of an intense research effort because determining the identity and regulation of these proteins is key to controlling A production. There appears to be one enzyme that predominates at each of the and cleavage sites (Fig. 1C). The predominant enzyme that cleaves APP at the-secretase site is BACE-1, whereas the predominant enzyme that cleaves the-secretase site is presenilin-1 (6, 7). In both cases, there are secondary enzymes, termed BACE-2 and presenilin-2, which can also cleave at this