Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer's disease
Caspase-6 role in apoptosis of human neurons, amyloidogenesis, and Alzheimer's disease
复制标题
DOI：
10.1074/jbc.274.33.23426
复制
发表时间：
1999-08-13
影响因子：
4.8
通讯作者：
Hammond, J
中科院分区：
文献类型：
--
作者：
LeBlanc, A;Liu, H;Hammond, J
神经元细胞死亡、神经元缠结和淀粉样β肽（A β）沉积描述了阿尔茨海默病（AD）病理学，但神经元损失与痴呆最相关。我们已经证明，A β的产生增加是神经元细胞凋亡的结果，这表明细胞凋亡激活了参与淀粉样前体蛋白（APP）加工的蛋白酶。在这里，我们研究了人类神经元细胞凋亡和APP加工中细胞死亡的关键效应物半胱天冬酶。我们发现，caspase-6被激活，负责神经细胞凋亡的血清剥夺。半胱天冬酶-6活性先于神经元凋亡的时间10小时，表明可能的活性而不随后的凋亡。抑制半胱天冬酶-6活性可防止血清剥夺介导的A β增加。胱天蛋白酶-6直接在C末端切割APP，并产生3 kDa的C末端片段（Capp 3）和含A β的6.5 kDa片段Capp6.5，其在血清剥夺的神经元中增加。脉冲追踪实验揭示了Capp6.5、细胞内A β和分泌的A β之间的受体-产物关系，表明潜在的替代淀粉样蛋白生成途径。Caspase-6酶原存在于成人脑组织中，并且在AD脑组织中检测到p10活性Caspase-6片段。这些结果表明，一个可能的替代途径APP淀粉样蛋白在人类神经元的加工和AD的神经元死亡的这一途径的潜在意义。
Neuronal cell death, neurofibrillary tangles, and amyloid beta peptide (A beta) deposition depict Alzheimer's disease (AD) pathology, but neuronal loss correlates best with dementia. We have shown that increased production of A beta is a consequence of neuronal apoptosis, suggesting that apoptosis activates proteases involved in amyloid precursor protein (APP) processing, Here, we investigate key effecters of cell death, caspases, in human neuronal apoptosis and APP processing. We find that caspase-6 is activated and responsible for neuronal apoptosis by serum deprivation. Caspase-6 activity precedes the time of commitment to neuronal apoptosis by 10 h, indicating possible activity without subsequent apoptosis, Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of A beta. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an A beta-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons. A pulse-chase experiment reveals a precursor-product relationship between Capp6.5, intracellular A beta, and secreted A beta, indicating a potential alternate amyloidogenic pathway. Caspase-6 proenzyme is present in adult human brain tissue, and the p10 active caspase-6 fragment is detected in AD brain tissue. These results indicate a possible alternate pathway for APP amyloidogenic processing in human neurons and a potential implication for this pathway in the neuronal demise of AD.