Amino-truncated amyloid beta-peptide (Abeta5-40/42) produced from caspase-cleaved amyloid precursor protein is deposited in Alzheimer's disease brain.
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.
Takeda
Kazuya
K
Department of Vascular Dementia Research, National Institute for Longevity Sciences, NCGG, Obu, Japan.
Araki
Wataru
W
Akiyama
Haruhiko
H
Tabira
Takeshi
T
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*
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