Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 <i>in vitro</i> and <i>in vivo</i>

TLDR

Epidemiological studies link cholesterol‑lowering statins to a reduced incidence of Alzheimer’s disease, and elevated Aβ42 levels together with the APOE ɛ4 allele are established risk factors. We show that simvastatin and lovastatin lower intracellular and extracellular Aβ42 and Aβ40 in hippocampal and cortical neuron cultures and markedly reduce cerebral Aβ levels in simvastatin‑treated guinea pigs, indicating that lipid modulation may underlie the protective effect of statins and offer a therapeutic avenue.

Abstract

Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated Aβ42 levels and the ɛ4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimer's disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of Aβ42 and Aβ40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral Aβ42 and Aβ40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimer's disease. Lowered levels of Aβ42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.