Amino-truncated amyloid beta-peptide (Abeta5-40/42) produced from caspase-cleaved amyloid precursor protein is deposited in Alzheimer's disease brain.
Amino-truncated amyloid beta-peptide (Abeta5-40/42) produced from caspase-cleaved amyloid precursor protein is deposited in Alzheimer's disease brain.
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发表时间：
2004
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通讯作者：
K. Takeda;W. Araki;H. Akiyama;T. Tabira
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作者：
K. Takeda;W. Araki;H. Akiyama;T. Tabira
半胱天冬酶激活和细胞凋亡与阿尔茨海默病（AD）有关。鉴于发现淀粉样前体蛋白（APP）在胞质区域经历半胱天冬酶介导的裂解，我们分析了表达野生型APP和半胱天冬酶裂解形式的APP（APPDeltaC）的人神经元和非神经元细胞中淀粉样β肽（Abeta）的产生。包括免疫沉淀/质谱法在内的生化分析显示，与野生型APP表达细胞相比，APP eltaC表达细胞分泌的氨基末端截短的A β 5 -40/42水平增加，而A β 1 -40/42水平降低。基于用BACE和α-分泌酶抑制剂处理细胞的数据，我们提出A β 5 -40/42来源于α-分泌酶样蛋白酶对APP的替代性β-切割。细胞凋亡诱导导致APP在野生型APP表达细胞中的这种替代切割。此外，用A β 5 -40/42的末端特异性抗体对AD脑进行免疫组化染色，发现淀粉样血管病的血管病变中存在肽沉积。这些数据共同表明，APP的半胱天冬酶切割导致AD脑中A β 5 -40/42的产生和沉积增加，并突出了氨基截短的A β在AD发病机制中的重要性。
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.