Takeda Kazuya, Araki Wataru, Akiyama Haruhiko, Tabira Takeshi
Department of Vascular Dementia Research, National Institute for Longevity Sciences, NCGG, Obu, Japan.
FASEB J. 2004 Nov;18(14):1755-7. doi: 10.1096/fj.03-1070fje. Epub 2004 Sep 13.
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.
半胱天冬酶激活和细胞凋亡与阿尔茨海默病（AD）有关。鉴于淀粉样前体蛋白（APP）在细胞质区域发生半胱天冬酶介导的切割这一发现，我们分析了表达野生型APP和半胱天冬酶切割形式的APP（APPDeltaC）的人神经元和非神经元细胞中β淀粉样肽（Aβ）的产生。包括免疫沉淀/质谱分析在内的生化分析表明，与表达野生型APP的细胞相比，表达APPDeltaC的细胞分泌的氨基末端截短的Aβ5-40/42水平升高，而Aβ1-40/42水平降低。基于用β分泌酶和α分泌酶抑制剂处理细胞的数据，我们提出Aβ5-40/42源自APP被α分泌酶样蛋白酶进行的替代性β切割。细胞凋亡诱导导致表达野生型APP的细胞中APP发生这种替代性切割。此外，用针对Aβ5-40/42的末端特异性抗体对AD脑进行免疫组织化学染色，发现血管病变中有淀粉样血管病的肽沉积。这些数据共同表明，APP的半胱天冬酶切割导致AD脑中Aβ5-40/42的产生和沉积增加，并突出了氨基截短的Aβ在AD发病机制中的重要性。
