Modulation of Alzheimers Amyloidosis by Statins: Mechanisms of Action

Abstract

Cerebral accumulation of Amyloid β (Aβ) peptides is an early event in establishing Alzheimers disease pathology. Based on epidemiological studies pointing to a link between cholesterol metabolism and Alzheimers disease (AD) as well as experimental evidence implicating cholesterol in the process of Aβ production and accumulation it is now believed that cholesterol-lowering therapies will be of value for AD prevention and / or treatment. Epidemiological studies have revealed that the use of statins for the treatment of hypercholesterolemia- and hyperlipidemia-related, coronary arterial disease is associated with a decreased prevalence or a decreased risk of developing AD. It is therefore necessary to test statins in one or more animal models of AD in order to establish which disease features are affected by statin treatment, the relative efficacy with which different statins modify these features and the mechanism(s) by which statins affect AD phenotypes. Here we discuss the results of a preclinical study aimed at determining the effects of atorvastatin (Lipitor-R) on brain Aβ deposition in the PSAPP transgenic mouse model of Alzheimers disease. The atorvastatininduced hypocholesterolemia was associated with a marked reduction in brain Aβ deposition and was also accompanied with a reduction in brain ApoE content. Based on our findings and the observations of others regarding the effects of statins on Aβ metabolism and taking into account the current knowledge of the various activities of statins, we propose a working hypothesis of the mechanisms by which statins modulate brain amyloidosis. Keywords: alzheimer disease, cholesterol, statin, atorvastatin, therapy, amyloidosis, anti-inflammatory, vascular