Non-steroidal anti-inflammatory drugs as anti-amyloidogenic compounds.
Amyloidosis is a clinical disorder caused by deposition of proteins that abnormally self-assemble into insoluble fibrils and impair organ function. More than 20 unrelated precursor proteins lose their native structure and misfold, leading to the formation of amyloid fibrils. The latter share cross-beta core structure in vivo and in vitro and gain abnormal functions. Local amyloid deposition occurs in the central nervous system in Alzheimer's disease (AD) and cerebral amyloid angiopathy. AD is the most common form of neurodegenerative disorder, with dementia in the elderly as well as dementia with Lewy bodies (DLB). Extracellular deposition of amyloid beta-peptide (Abeta) has been implicated as a critical step in the pathogenesis of AD. Involvement of neuroinflammation and microglial activation has been emphasized in the AD brain. Recent epidemiological studies have shown that long-term therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delayed the onset of AD. We review epidemiological studies of anti-AD effects of NSAIDs, experimental studies of anti-amyloidogenic as well as anti-inflammatory effects of NSAIDs, and recent clinical trials for AD with NSAIDs. We refer to the anti-fibrillogenic and fibril-destabilizing activities of NSAIDs for other proteins that can aggregate and form amyloid-like fibrils, including alpha-synuclein in DLB. The anti-amyloidogenic properties of some NSAIDs provide new insights for future therapeutic and preventative opportunities for AD and other amyloidoses, and protein-misfolding disorders.
Hirohata
Mie
M
Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan.
Ono
Kenjiro
K
Yamada
Masahito
M
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism / Q000517:prevention & control; D000682:Amyloid / Q000378:metabolism*; D000686:Amyloidosis / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002986:Clinical Trials as Topic; D006801:Humans; D015394:Molecular Structure; D017510:Protein Folding; D013329:Structure-Activity Relationship
D000682:Amyloid; D000894:Anti-Inflammatory Agents, Non-Steroidal