title: [A pathogenic mechanism of N-terminally pyroglutamylated Aβ and possible application of Alzheimer's disease by inhibition of the pyroglutamylation].
abstract: Aggregation and accumulation of amyloid-β peptide (Aβ) in the brain are triggering events leading to the pathological cascade of Alzheimer's disease (AD). Aβ accumulates in AD brains and forms amyloid plaques, which consist mostly of amino-terminally truncated and/or modified Aβs, among which Aβ3pyroglutamate (Aβ3pE) is a major product. Thus, the N-terminal structures of accumulated species of Aβ are different from those secreted from neurons. Aβ3pE-42 is more hydrophobic, more easily self-aggregated (250-fold), and is more resistant to proteolytic degradation (4-fold) than Aβ1-42. Therefore, Aβ3pE appears to act as a seed for the formation of oligomers and amyloid plaques. Aβ is physiologically degraded via the neprilysin-mediated pathway in the brain. However, if neprilysin activity is low, a compensatory metabolic pathway is up-regulated, in which exopeptidases, such as aminopeptidase or dipeptidyl peptidase, and glutaminyl cyclase (QC) may be involved, generating Aβ3pE. It is reported that QC is up-regulated with AD development. Recent study revealed that administration of synthetic QC inhibitor reduced total amyloid burden in the brains of APP transgenic mice (Tg2576) via inhibition of Aβ3pE production and also alleviated impaired cognitive function. Thus, inhibition of Aβ3pE formation appears to be a novel target for therapy and prevention of AD.
authors.affiliation: Graduate School of Biomedical Sciences, Nagasaki University.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Masashi
authors.initials: M
authors.lastname: Asai
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000517:prevention & control*; D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D006801:Humans; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D011761:Pyrrolidonecarboxylic Acid