title: Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease.
abstract: Amyloid-β peptide (Aβ) and tau are major components of senile plaques and neurofibrillary tangles, respectively, deposited in the brains of Alzheimer disease (AD) patients. Aβ is derived from amyloid-β precursor protein that is sequentially cleaved by two aspartate proteases, β- and γ-secretases. Secreted Aβ is then catabolized by several proteases. Several lines of evidence suggest that accumulation of Aβ by increased production or decreased degradation induces the tau-mediated neuronal toxicity and symptomatic manifestations of AD. Thus, the dynamics of cerebral Aβ, called as "Aβ economy", would be the mechanistic basis of AD pathogenesis. Partial loss of γ-secretase activity leads to the increased generation of toxic Aβ isoforms, indicating that activation of γ-secretase would provide a beneficial effect for AD. After extensive discovery and development efforts, BACE1, which is a β-secretase enzyme, has emerged as a prime drug target for lowering brain Aβ levels. Recent studies revealed the decreased clearance of Aβ in sporadic AD patients, suggesting the importance of the catabolic mechanism in the pathogenesis of AD. I will discuss with these proteolytic mechanisms involved in the regulation of Aβ economy, and development of effective treatment and diagnostics for AD.
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007339:Insulysin / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D059748:Proteolysis; D015398:Signal Transduction; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D007527:Isoenzymes; C054369:MAPT protein, human; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; C082472:KLK7 protein, human; D007610:Kallikreins; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D015260:Neprilysin; D007339:Insulysin
keywords: Alzheimer disease; Amyloid-β peptide; Degradation; Membrane protein; Protease; Secretase