Statin-Like Drugs for the Treatment of Brain Cholesterol Loss in Alzheimers Disease

Abstract

Aging is one of the most significant risk factors for neurological disorders including Alzheimer's Disease (late-onset AD and sporadic AD), the most common form of dementia. AD is characterized by progressive atrophy and loss of neurons resulting in cognitive deficits, confusion and dementia, culminating in childlike helplessness and death. One of the major pathological hallmarks of the disease are amyloid plaques, composed primarly of insoluble fibrils of Abeta peptide: this molecule derives from the processing of the transmembrane amyloid precursor protein (APP) by different secretases and its production is a physiological event, but the anormal increase in Abeta levels appears to be toxic both in vitro and in vivo. Being APP cleavage a membrane event the involvement of lipids in alterations of this cleavage is assumable. Cholesterol is the most abundant lipid in cellular membranes and is an essential component of them, determining the fluidity and biophysical properties. In fact, genetic studies of the risk of AD have reported association with polymorphism in some cholesterol related genes like the allele epsilon4 of the apolipoprotein E, cholesterol 24-hydroxylase (CYP46A1), ATP-binding cassette transporter a1 (ABCA1) and the lipoprotein receptor-related protein (LRP). Moreover a recent publication shows a downregulation of Seladin-1 (which catalyze the last step of cholesterol biosynthesis) in affected neurons in Alzheimer's Disease. Post-mortem analysis of AD brains reveal a loss in cholesterol content and this make the therapeutical use of statin-like drugs quite a lot controversial. Taking together their clinical trials results and the large body of literature regarding lipid profile alterations in AD, it is actually unclear how much these agents can be helpful or not for affected patients.