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

Abstract

Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated A␤42 levels and the 4 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 A␤42 and A␤40 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 A␤42 and A␤40 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 A␤42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.A part from age, environmental factors have only slight influence on the incidence of Alzheimer's disease (AD). Very recently, two independent reports showed a strong decrease in the incidence of AD and dementia for patients that were treated with statins (1, 2). Both studies were retrospective, and statins were not given in any relation to dementia. Usually statins are prescribed for treatment of elevated serum cholesterol levels in patients. They reduce cholesterol levels by inhibiting the bottleneck enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. They are widely used drugs, well characterized and considered to be very safe for long-time treatment, and approved for use in elderly patients (3, 4).The 4 allele of the apolipoprotein E (apoE) is the major genetic risk factor for AD (5). Several lines of evidence indicate that apoE 4 and statins have a related influence on AD. The normal cellular function of apoE is uptake and delivery of lipids. The isoform apoE 4 correlates with an increased risk for atherosclerosis (6) and amyloid plaque formation (7). Moreover, elevated cholesterol uptake increases amyloid plaque formation or amyloid deposition (8,9). This correlation may be extended to A␤ production, since cellular cholesterol levels affect neuronal A␤ production in vitro (10). Initially, A␤ has been a focus of AD research, because it was found to be the major constituent of the amyloid plaque. It is unknown whether the amyloid plaque is actively involved in the neurodegenerative process in AD or instead is a consequence of the disease process. More recently, however, A␤ has been a focus of AD research not because of it presence in the amyloid plaque, but because an overproduction of a minor A␤ isoform, A␤42, is linked to all identified inherited forms of AD (11-13).A␤ is produced during normal cellular processing of the Alzheimer amyloid precursor protein (APP) (14) by ␤-secretase and ␥-secretase (15). While the majority of all A␤ isoforms produced is A␤40, Ϸ10% of total A␤ ...

Using model membranes for the study of amyloid beta:lipid interactions and neurotoxicity

“…A point of further interest was the differing behavior of the inhibitors between aqueous and GM1-mediated environments . Other work using DRMs have shown that Simvastatin, a cholesterol reducing drug, decreased Ab levels both in vivo and in vitro (Fassbender et al, 2001), complementing a report by Kalvodova et al (2005) who, using giant liposomes, demonstrated that cholesterol stimulated proteolytic activity of BACE, known to increase Ab levels.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…By reducing cellular cholesterol level through lovastatin and methyl‐β‐cyclodextrin, the formation of Aβ is inhibited (Hartmann, Kuchenbecker, & Grimm, 2007; Simons et al, 1998; Vetrivel & Thinakaran, 2010). Cholesterol levels can also directly regulate β‐secretase‐mediated production of Aβ (Fassbender et al, 2001; Simons et al, 1998; Wahrle et al, 2002). Inclusion of cholesterol or sphingolipids in phosphatidylcholine‐containing vesicles leads to increased γ‐secretase activity (Osawa et al, 2008; Osenkowski, Ye, Wang, Wolfe, & Selkoe, 2008).…”

Cholesterol and Alzheimer's disease: A still poorly understood correlation

“…More recently, this cholesterolinduced memory impairment has been correlated with a loss of dendritic integrity, cholinergic dysfunction, inflammation (43), enhanced cortical Ab and phosphorylated tau (44), all indications which resemble an AD-like pathology. In line with such observations, cholesterol-lowering drugs (i.e., statins) were found to reduce cerebral Ab (21,45,46), phosphorylated tau (46), inflammation (45), and memory deficits (46,47) in a variety of animal models. Whether statins act in the brain simply by lowering cholesterol biosynthesis or by a different mechanism, however, still remains an open question.…”

“…Using genetic, biochemical, and metabolic approaches, it was found that cholesteryl esters are directly correlated with Ab production, as increasing levels of cholesteryl esters enhanced Ab release in cultured cells, whereas pharmacological inhibition of ACAT led to the reduction of both cholesteryl esters and Ab production (18,19). Accordingly, the inhibition of the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, a key enzyme in the cholesterol de novo synthesis, reduced both intracellular and extracellular Ab levels (20,21).…”