Mitochondria, cholesterol and amyloid β 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 (A beta) in the onset and progression of the disease. The amyloidogenic processing of amyloid precursor protein into pathogenic A beta fragments is thought to occur in specific domains of the plasma membrane and favored by cholesterol enrichment. Intracellular A beta accumulation is known to induce oxidative stress, predominantly via mitochondria targeting of toxic A beta. Recent evidence using mouse models of cholesterol loading has demonstrated that the specific mitochondrial cholesterol pool sensitizes neurons to A beta-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 A beta-mediated neurotoxicity and inflammation. Thus, these novel data expand the pathogenic role of cholesterol in AD indicating that in addition to fostering A beta generation, mitochondrial cholesterol determines A beta neurotoxicity via mGSH regulation.