The mitochondrial secret(ase) of Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory and cognition and pathologically by extracellular amyloid-beta (Abeta) deposits and intraneuronal aggregates of hyperphosphorylated tau. Since its proposal in 1992, the amyloid cascade hypothesis implicates Abeta overproduction as a causative event in disease pathogenesis, and this thinking has predominated the field's understanding of AD pathogenesis and the development of potential therapeutics (i.e., Abeta-reducing agents). Though Abeta has been shown to induce AD pathology, unanswered questions for sporadic AD development suggests this hypothesis is best applied to familial disease only. The more recent mitochondrial cascade hypothesis is supported by data showing that early impairments of mitochondrial dysfunction and oxidative stress may precede Abeta overproduction and deposition. However, the development of Abeta-reducing agents continues. Unfortunately, these agents have not been efficiently tested for their effect on one of the earliest AD pathologies, i.e., mitochondrial dysfunction. This paper will review supporting data for the amyloid and mitochondrial cascade hypotheses, reports of the effects of secretase inhibitors on AD-phenotypic cells and animals, and begin to look at a potential role for gamma-secretase, which is localized to mitochondria, in AD-related mitochondrial dysfunction.
Young
Kisha J
KJ
Neuroscience Graduate Program and Medical Scientist Training Program, University of Virginia School of Medicine, Charlottesville, VA, USA.
Bennett
James P
JP
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D028361:Mitochondrial Diseases / Q000150:complications / Q000473:pathology; D008954:Models, Biological
D016229:Amyloid beta-Peptides; D053829:Amyloid Precursor Protein Secretases