title: Amino-truncated amyloid beta-peptide (Abeta5-40/42) produced from caspase-cleaved amyloid precursor protein is deposited in Alzheimer's disease brain.
abstract: Caspase activation and apoptosis are implicated in Alzheimer's disease (AD). In view of the finding that the amyloid precursor protein (APP) undergoes caspase-mediated cleavage in the cytoplasmic region, we analyzed amyloid beta-peptide (Abeta) production in human neuronal and nonneuronal cells expressing wild-type APP and the caspase-cleaved form of APP (APPDeltaC). Biochemical analyses, including immunoprecipitation/mass spectrometry, revealed that APPDeltaC-expressing cells secrete increased levels of amino-terminally truncated Abeta5-40/42 and reduced levels of Abeta1-40/42, compared with wild-type APP-expressing cells. We propose that Abeta5-40/42 is derived from alternative beta-cleavage of APP by alpha-secretase-like protease(s), based on data from treatment of cells with inhibitors of BACE and alpha-secretase. Apoptosis induction resulted in this alternative cleavage of APP in wild-type APP-expressing cells. Moreover, immunohistochemical staining of the AD brain with an end-specific antibody to Abeta5-40/42 revealed peptide deposits in vascular lesions with amyloid angiopathy. The data collectively suggest that caspase cleavage of APP leads to increased production and deposition of Abeta5-40/42 in the AD brain, and highlight the significance of amino-truncated Abeta in the pathogenesis of AD.
authors.affiliation: Department of Vascular Dementia Research, National Institute for Longevity Sciences, NCGG, Obu, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takeda
authors.forename: Wataru
authors.initials: W
authors.lastname: Araki
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tabira
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D020169:Caspases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010446:Peptide Fragments / Q000032:analysis / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C500436:amyloid beta-peptide (5-40); C500437:amyloid beta-peptide (5-42); D020169:Caspases