Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer's disease.
Alzheimer's disease (AD) is a late-onset dementia that is characterized by the loss of memory and an impairment of multiple cognitive functions. Advancements in molecular, cellular, and animal model studies have revealed that the formation of amyloid beta (Abeta) and other derivatives of the amyloid precursor protein (APP) are key factors in cellular changes in the AD brain, including the generation of free radicals, oxidative damage, and inflammation. Recent molecular, cellular, and gene expression studies have revealed that Abeta enters mitochondria, induces the generation of free radicals, and leads to oxidative damage in post-mortem brain neurons from AD patients and in brain neurons from cell models and transgenic mouse models of AD. In the last three decades, tremendous progress has been made in mitochondrial research and has provided significant findings to link mitochondrial oxidative damage and neurodegenerative diseases such as AD. Researchers in the AD field are beginning to recognize the possible involvement of a mutant APP and its derivatives in causing mitochondrial oxidative damage in AD. This article summarizes the latest research findings on the generation of free radicals in mitochondria and provides a possible model that links Abeta proteins, the generation of free radicals, and oxidative damage in AD development and progression.
Reddy
P Hemachandra
PH
Neurogenetics Laboratory, Neurological Sciences Institute, Oregon Health & Science University, Beaverton, Oregon 97006, USA. reddyh@oshu.edu
D000375:Aging; D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002986:Clinical Trials as Topic; D018450:Disease Progression; D005609:Free Radicals / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D005609:Free Radicals; D017382:Reactive Oxygen Species