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Amino‐truncated amyloid β‐peptide (Aβ5‐40/42) 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 β‐peptide (Aβ) production in human neuronal and nonneuronal cells expressing wild‐type APP and the caspase‐cleaved form of APP (APPΔC). Biochemical analyses, including immunoprecipitation/mass spectrometry, revealed that APPΔC‐expressing cells secrete increased levels of amino‐terminally truncated Aβ5‐40/42 and reduced levels of Aβ1‐40/42, compared with wild‐type APP‐expressing cells. We propose that Aβ5‐40/42 is derived from alternative β‐cleavage of APP by α‐secretase‐like protease(s), based on data from treatment of cells with inhibitors of BACE and α‐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 Aβ5‐40/42 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 Aβ5‐40/42 in the AD brain, and highlight the significance of amino‐truncated Aβ in the pathogenesis of AD.