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P2‐212: Overexpression of Bcl‐2 in APP transgenic mice reduces amyloid pathology
Author(s) -
Poon Wayne W.,
Carlos Anthony J.,
Cotman Carl W.,
Rohn Troy T.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1261
Subject(s) - genetically modified mouse , tau pathology , tangle , transgene , pathology , apoptosis , caspase , neurofibrillary tangle , hippocampus , amyloid (mycology) , amyloid precursor protein , alzheimer's disease , neuroscience , biology , microbiology and biotechnology , programmed cell death , senile plaques , medicine , disease , biochemistry , gene , mathematics , pure mathematics
lysosomal membrane permeabilization is regulated, but the lipid composition of the lysosomal membrane has a key role for lysosomal stability, and might influence the susceptibility to lysosomal leakage. The aim of this study was to investigate the effect of lysosomal cholesterol accumulation on lysosomal stability and cellular sensitivity to apoptosis. Methods: To mimic the NPC phenotype in a cell culture model, human fibroblasts and Chinese hamster ovary (CHO) cells have been treated with 3-b-[2-(diethylamino)ethoxy]androst-5-en-17-one (U18666A), a drug known to interfere with intracellular cholesterol transport and results in cholesterol accumulation in late endosomes and lysosomes. Genetically modified CHO cells (NPC1) was used to confirm the results. Results: Lysosomal cholesterol accumulation, induced by genetic deficiency of NPC1 or U18666A-treatment, did not affect cell viability, but was associated with an upregulation of the lysosomal system with increased expression cathepsin D and LAMP-2. Cholesterol accumulation rescued cells from apoptosis induced by exposure to staurosporine or the lyosomotropic detergent O-methyl-serine dodecylamine hydrochloride (MSDH). Both these inducers are known to promote apoptosis via the lysosomal death pathway in human fibroblast, and accordingly decreased sensitivity to apoptosis induction was associated with diminished lysosomal leakage. The cholesterol content of lysosomes correlated to their susceptibility to lysosomal membrane permeabilization, suggesting that cholesterol regulate lysosomal stability. Moreover, APP over expressing CHO cells were rescued from lysosome-dependent cell death induced by MSDH or ammonium chloride by pretreatment with U18666A, indicating that lysosomal cholesterol accumulation confer significant protection also in an Alzheimer model. Conclusions: We suggest that cholesterol accumulation in lysosomes attenuates the lysosomal death pathway by increasing lysosomal membrane stability.