Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer's brains
Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer's brains
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DOI：
10.1007/s00401-013-1111-z
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发表时间：
2013-06-01
影响因子：
12.7
通讯作者：
Duyckaerts, Charles
中科院分区：
文献类型：
--
作者：
Ando, Kunie;Brion, Jean-Pierre;Duyckaerts, Charles
PICALM是一种网格蛋白衔接蛋白，在所有细胞类型中的网格蛋白介导的内吞作用中起重要作用。近年来，全基因组关联研究发现PICALM基因单核苷酸多态性是晚发性阿尔茨海默病（LOAD）的遗传危险因素。我们用几种抗PICALM抗体通过蛋白质印迹法分析了人脑提取物中PICALM的表达模式。我们发现PICALM在AD样本中异常切割，并且AD大脑中未切割的65-75 kDa全长PICALM种类的水平显着降低。在体外证明了内源性钙蛋白酶或半胱天冬酶激活后人PICALM的切割。免疫组化显示，PICALM与神经元缠结原位相关，与LOAD、家族性AD和唐氏综合征病例中的构象异常和过度磷酸化tau蛋白共定位。PHF-tau蛋白与PICALM共免疫沉淀。LOAD中PICALM在小胶质细胞中高度表达。这些观察结果表明PICALM与AD tau病理学的发展相关。PICALM裂解可能导致AD的内吞功能障碍。
PICALM, a clathrin adaptor protein, plays important roles in clathrin-mediated endocytosis in all cell types. Recently, genome-wide association studies identified single nucleotide polymorphisms in PICALM gene as genetic risk factors for late-onset Alzheimer disease (LOAD). We analysed by western blotting with several anti-PICALM antibodies the pattern of expression of PICALM in human brain extracts. We found that PICALM was abnormally cleaved in AD samples and that the level of the uncleaved 65-75 kDa full-length PICALM species was significantly decreased in AD brains. Cleavage of human PICALM after activation of endogenous calpain or caspase was demonstrated in vitro. Immunohistochemistry revealed that PICALM was associated in situ with neurofibrillary tangles, co-localising with conformationally abnormal and hyperphosphorylated tau in LOAD, familial AD and Down syndrome cases. PHF-tau proteins co-immunoprecipitated with PICALM. PICALM was highly expressed in microglia in LOAD. These observations suggest that PICALM is associated with the development of AD tau pathology. PICALM cleavage could contribute to endocytic dysfunction in AD.