No abstract

beta-Amyloid (Abeta) protein is the major constituent of senile plaques and cerebrovascular deposits characteristic of Alzheimer's disease (AD). The causal relationship between Abeta and AD-specific lesions like neurodegeneration and atrophy is still not known. The present article summarizes our studies indicating that rather low concentrations of Abeta significantly alter the fluidity of cell membranes and subcellular fractions from different tissues and different species including humans, as a possible initial step of its biological effects. Using different fluorescent probes our data show clearly that Abeta peptides specifically disturb the acyl-chain layer of cell membranes in a very distinct fashion. By contrast, membrane properties at the level of the polar heads of the phospholipid bilayer at the interface with membrane proteins are much less affected.

Growing evidence indicates that membrane cholesterol is involved in the development of Alzheimer's disease. Therefore, the availability of pharmacological strategies to modify brain cholesterol is of increasing importance. Accordingly, we investigated the effects of the HMG-CoA reductase inhibitor lovastatin on brain cholesterol levels in vivo. Brain cholesterol was significantly decreased by lovastatin treatment (100 mg/kg/day) in 1- and 12-month-old C57BL/6J mice. Reduced brain cholesterol was associated with decreased pyrene-excimer fluorescence, indicating altered membrane function. Lovastatin had no effect on brain cholesterol ApoE-/- mice. Peripheral cholesterol levels were not affected by lovastatin in all three groups of mice. We demonstrate for the first time that lovastatin represents a valid pharmacological tool to significantly modulate brain cholesterol levels.

Growing evidence indicates a significant linkage between Abeta and cholesterol metabolism, although the exact role of cholesterol in brain aging and in the pathogenesis of AD is still unknown. Recently, in vitro and in vivo modification of cell cholesterol and its effect on Abeta-generation became a straight focus in the research of AD. In the present study, we discretely modulated the cholesterol contents of neuronal membranes from mice of different ages in vivo and in vitro using lovastatin and methyl-beta-cyclodextrin, respectively. The aim of the study was to investigate whether this modulation results in altered physico-chemical membrane properties. Therefore, we performed membrane fluidity measurements using three fluorescent dyes labeling different membrane regions. Furthermore, we evaluated the effects of cholesterol modulation on the membrane disturbing properties of Abeta. Modulation of membrane cholesterol content in vivo and in vitro was linked to changes in membrane properties. Very interestingly, cholesterol content of in vitro modulated neuronal membranes was negatively correlated with the membrane perturbing effects of Abeta.

Growing evidence suggests that cellular cholesterol homeostasis is causally involved in different steps leading to pathological events in the brain of Alzheimer's Disease (AD) patients. It was previously demonstrated that the processing of the amyloid beta-peptide precursor protein (APP) is modulated by pronounced alterations in cellular cholesterol levels using statins or cholesterol extracting agents. However, a cholesterol-rich diet was found to enhance amyloid beta-peptide (Abeta) burden in the brain of transgenic mice without clearly affecting total brain cholesterol levels. Recent retrospective epidemiological studies have reported that the use of statins potentially suppresses the development of AD. Although some HMG-CoA reductase inhibitors seem to influence the central cholesterol pool in vivo, the above epidemiological findings are probably not linked to statin-induced changes in brain membrane cholesterol levels per se since not all statins active in preventing AD enter the central nervous system (CNS). Recently, we reported that different statins, regardless of their brain availability, induce alterations in cellular cholesterol distribution in the brain. Such pleiotropic, cholesterol-synthesis independent statin effects might be indirect and are possibly mediated at the blood-brain barrier (BBB) via nitric oxide (NO) or apolipoprotein E (ApoE).