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Cellular mechanisms of lipid mediated regulation of Alzheimers disease Abeta secretases and presenilin localization

, : Cellular mechanisms of lipid mediated regulation of Alzheimers disease Abeta secretases and presenilin localization. Society for Neuroscience Abstracts 27(2): 1518

Cholesterol lowering reduces in vivo and in vitro the production of Abeta42 peptides (Fassbender et. al PNAS 2001). Retrospective evidences suggest a strong protective potential of cholesterol reduction in humans. APP is processed by the consecutive action of BACE I and the presenilin containing gamma-secretase complex to Abeta. Alternatively, APP is processed by alpha secretase. We have characterized the influence of cholesterol levels, cellular compartments and intracellular transport on APP secretases. Unexpectedly, cholesterol depletion methods revealed a complex lipid dependent regulation of APP secretases. APP-beta-secretase activity was reduced upon cholesterol depletion and this was further aggravated by an additive but apparently independent reduction in APP-gamma-secretase activity. APP-secretases resulting in Abeta 42 production, but not Abeta40 production, required a largely undisturbed cholesterol content/HMG-CoA reductase activity in the early secretory pathway, most likely the ER. This is unexpected because the early secretory pathway/ER cholesterol content is very low. Unequal disturbances in the cholesterol content of the early versus later secretory pathway resulted in alterations in the otherwise constant intracellular Abeta40/42 ratio. Partial inhibition of intracellular cholesterol transport resulted in reduced APP-beta-secretase activity, but increased APP-gamma-secretase dependent Abeta production, as well as altered presenilin localization. Further these effects are not limited to cholesterol, but rather may be extended to other lipids.


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