Mitochondria, cholesterol and amyloid beta peptide: a dangerous trio in Alzheimer disease.
The molecular mechanisms of Alzheimer's disease (AD) are not fully understood. Extensive evidence from experimental models has involved the overgeneration and accumulation of toxic amyloid beta peptides (Abeta) in the onset and progression of the disease. The amyloidogenic processing of amyloid precursor protein into pathogenic Abeta fragments is thought to occur in specific domains of the plasma membrane and favored by cholesterol enrichment. Intracellular Abeta accumulation is known to induce oxidative stress, predominantly via mitochondria targeting of toxic Abeta. Recent evidence using mouse models of cholesterol loading has demonstrated that the specific mitochondrial cholesterol pool sensitizes neurons to Abeta-induced oxidant cell death and caspase-independent apoptosis due to selective mitochondrial GSH (mGSH) depletion induced by cholesterol-mediated perturbation of mitochondrial membrane dynamics. mGSH replenishment by permeable precursors such as glutathione ethyl ester protected against Abeta-mediated neurotoxicity and inflammation. Thus, these novel data expand the pathogenic role of cholesterol in AD indicating that in addition to fostering Abeta generation, mitochondrial cholesterol determines Abeta neurotoxicity via mGSH regulation.
Liver Unit and Centro de Investigaciones Biomédicas Esther Koplowitz, IMDiM, Hospital Clínic i Provincial and CIBEREHD, IDIBAPS, and Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain. acibam@iibb.csic.es
Anna
A
Colell
Anna
A
Fernández
José C
JC
Fernández-Checa
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D005732:Gangliosides / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational
D016229:Amyloid beta-Peptides; D005732:Gangliosides; D002784:Cholesterol; D005978:Glutathione