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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␤ ...

Microglial activation is a key feature in Alzheimer’s disease and is considered to contribute to progressive neuronal injury by release of neurotoxic products. The innate immune receptor Toll-like-receptor 4 (TLR4), localized on the surface of microglia, is a first-line host defense receptor against invading microorganisms. Here, we show that a spontaneous loss-of-function mutation in the Tlr4 gene strongly inhibits microglial and monocytic activation by aggregated Alzheimer amyloid peptide resulting in a significantly lower release of the inflammatory products IL-6, TNFα and nitric oxide. Treatment of primary murine neuronal cells with supernatant of amyloid peptide-stimulated microglia demonstrates that Tlr4 contributes to amyloid peptide-induced microglial neurotoxicity. In addition, stimulation experiments in transfected HEK293 cells allowed to define a tri-molecular receptor complex consisting of TLR4, MD-2 and CD14 necessary for full cellular activation by aggregated amyloid peptide. A clinical relevance of these findings is supported by a marked upregulation of Tlr4 mRNA in APP transgenic mice and by an increased expression of TLR4 in Alzheimer’s disease brain tissue associated with amyloid plaque deposition. Together, these observations provide the first evidence for a role of the key innate immune receptor, TLR4, in neuroinflammation in Alzheimer’s disease.