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Mitochondria, cholesterol and amyloid beta peptide: a dangerous trio in Alzheimer disease.
- Source :
-
Journal of bioenergetics and biomembranes [J Bioenerg Biomembr] 2009 Oct; Vol. 41 (5), pp. 417-23. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Alzheimer Disease pathology
Animals
Apoptosis
Disease Models, Animal
Gangliosides metabolism
Glutathione metabolism
Humans
Mice
Models, Biological
Oxidative Stress
Protein Processing, Post-Translational
Alzheimer Disease etiology
Alzheimer Disease metabolism
Amyloid beta-Peptides metabolism
Cholesterol metabolism
Mitochondria metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1573-6881
- Volume :
- 41
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of bioenergetics and biomembranes
- Publication Type :
- Academic Journal
- Accession number :
- 19784764
- Full Text :
- https://doi.org/10.1007/s10863-009-9242-6