Amino‐truncated amyloid β‐peptide (Aβ5‐40/42) produced from caspase‐cleaved amyloid precursor protein is deposited in Alzheimer’s disease brain
Amino‐truncated amyloid β‐peptide (Aβ5‐40/42) produced from caspase‐cleaved amyloid precursor protein is deposited in Alzheimer’s disease brain
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由 caspase 裂解的淀粉样前体蛋白产生的氨基截短的淀粉样 β 肽 (Aβ5-40/42) 沉积在阿尔茨海默病的大脑中
DOI：
10.1096/fj.03-1070fje
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
T. Tabira
中科院分区：
文献类型：
--
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APP（APPΔC）的人神经元和非神经元细胞中淀粉样β肽（Aβ）的产生。包括免疫沉淀/质谱分析在内的生化分析显示，与野生型APP表达细胞相比，APPΔC表达细胞分泌的氨基末端截短的Aβ5 - 40/42水平升高，Aβ1 - 40/42水平降低。基于BACE和α-分泌酶抑制剂处理细胞的数据，我们认为Aβ5 - 40/42来源于α-分泌酶样蛋白酶对APP的替代性β-裂解。凋亡诱导导致野生型APP表达细胞中APP的这种替代切割。此外，用Aβ5 - 40/42末端特异性抗体对AD脑进行免疫组织化学染色，发现淀粉样血管病血管病变中存在肽沉积。这些数据共同表明，APP的半胱天冬酶裂解导致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。
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.
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影响因子：
64.5
作者：
F. Gervais;D. Xu;G. Robertson;J. Vaillancourt;Y. Zhu;J. Huang;A. LeBlanc;D. Smith;M. Rigby;M. Shearman;E. Clarke;H. Zheng;L. V. D. van der Ploeg;S. C. Ruffolo;N. Thornberry;S. Xanthoudakis;R. Zamboni;S. Roy;D. Nicholson
通讯作者：
F. Gervais;D. Xu;G. Robertson;J. Vaillancourt;Y. Zhu;J. Huang;A. LeBlanc;D. Smith;M. Rigby;M. Shearman;E. Clarke;H. Zheng;L. V. D. van der Ploeg;S. C. Ruffolo;N. Thornberry;S. Xanthoudakis;R. Zamboni;S. Roy;D. Nicholson
影响因子：
82.9
作者：
D. Lu;S. Rabizadeh;S. Chandra;R. Shayya;L. Ellerby;X. Ye;G. Salvesen;E. Koo;D. Bredesen
通讯作者：
D. Lu;S. Rabizadeh;S. Chandra;R. Shayya;L. Ellerby;X. Ye;G. Salvesen;E. Koo;D. Bredesen
影响因子：
6
作者：
Rohn, TT;Head, E;Cribbs, DH
通讯作者：
Cribbs, DH
DOI：
--
发表时间：
1999
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
R. Perez;S. Soriano;J. D. Hayes;B. Ostaszewski;W. Xia;D. Selkoe;X. Chen;G. Stokin;E. Koo
通讯作者：
R. Perez;S. Soriano;J. D. Hayes;B. Ostaszewski;W. Xia;D. Selkoe;X. Chen;G. Stokin;E. Koo
DOI：
10.1042/bj3570787
发表时间：
2001-08
期刊：
The Biochemical journal
影响因子：
--
作者：
Barbara E. Slack;Leona K. Ma;Ching Ching Seah-Ching
通讯作者：
Barbara E. Slack;Leona K. Ma;Ching Ching Seah-Ching