engleski

Cholesterol levels modulate formation of AICD as well as Abeta

There is growing interest in the potential contribution of cholesterol to the pathogenesis of Alzheimer’ s disease (AD). Biochemical, epidemiological and genetic studies link cholesterol levels to amyloid-beta peptide (Abeta) production and the onset of AD pathology. The link between cholesterol and Abeta has recently been revealed in Niemann Pick Type C (NPC) diseases as well as AD. Intracellular cholesterol accumulation in NPC disease causes increased Abeta formation and shifts presenilin 1 (PS1) localization to early/late endosomes. The aim of this work was to analyze whether cholesterol-effect on APP processing is specific for A formation or modulates the generation of APP signaling molecule – the APP IntraCellular Domain (AICD) as well. Since generation of AICD, like Abeta, is presenilin-dependent, we hypothesized that changing cholesterol levels modulates the levels of AICD as well as Abeta. We have previously shown that the two topologically different gamma-secretase cleavages of APP at gamma40/42 and epsilon-site, to liberate Abeta and AICD, are not tightly linked. Comparing the effect of cholesterol on Abeta and AICD production would thus further our understanding of the mechanisms of their formation. Our results show that cholesterol depletion in CHOwt and in CHO-NPC null cells caused a substantial decrease of secreted Abeta and AICD. Surprisingly, Abeta and AICD were reduced to a similar levels, although the amount of free cholesterol substantially differed in these cells. Finding that cholesterol levels regulate Abeta biogenesis and APP signaling is important both for treating Alzheimer’ s disease as well as for understanding normal APP function.

Alzheimer's disease; Cholesterol; dementia; neurodegeneration

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