Levey A I, Heilman C J, Lah J J, Nash N R, Rees H D, Wakai M, Mirra S S, Rye D B, Nochlin D, Bird T D, Mufson E J
Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Ann Neurol. 1997 Jun;41(6):742-53. doi: 10.1002/ana.410410610.
Mutations of the presenilin PS1 and PS2 genes are closely linked to aggressive forms of early-onset (< 60 years) familial Alzheimer's disease. A highly specific monoclonal antibody was developed to identify and characterize the native PS1 protein. Western blot analyses revealed a predominant 32-kd immunoreactive polypeptide in a variety of samples, including PC12 cells transfected with human PS1 complementary DNA, brain biopsy specimens from demented patients, and postmortem samples of frontal neocortex from early-onset familial Alzheimer's disease cases (PS1 and PS2), late-onset sporadic Alzheimer's disease cases, and cases of other degenerative disorders. This truncated polypeptide contains the N-terminus of PS1 and appeared unchanged across cases. In 2 early-onset cases linked to missense mutations in the PS1 gene, a PS1 immunoreactive protein (approximately 49 kd) accumulated in the frontal cortex. This protein was similar in size to full-length PS1 protein present in transfected cells overexpressing PS1 complementary DNA, and in lymphocytes from an affected individual with a deletion of exon 9 of the PS1 gene, suggesting that mutations of the PS1 gene peturb the endoproteolytic processing of the protein. Immunohistochemical studies of control brains revealed that PS1 is expressed primarily in neurons, with the protein localized in the soma and dendritic processes. In contrast, PS1 showed striking localization to the neuropathology in early-onset familial Alzheimer's disease and sporadic Alzheimers' disease cases. PS1 immunoreactivity was present in the neuritic component of senile plaques as well as in neurofibrillary tangles. Localization of PS1 immunoreactivity in familial and sporadic Alzheimer's disease suggests that genetically heterogeneous forms of the disease share a common pathophysiology involving PS1 protein.
早老素PS1和PS2基因的突变与侵袭性早发型（<60岁）家族性阿尔茨海默病密切相关。已开发出一种高度特异性的单克隆抗体来鉴定和表征天然PS1蛋白。蛋白质印迹分析显示，在多种样品中存在一种主要的32-kd免疫反应性多肽，这些样品包括转染了人PS1互补DNA的PC12细胞、痴呆患者的脑活检标本，以及早发型家族性阿尔茨海默病病例（PS1和PS2）、晚发型散发性阿尔茨海默病病例和其他退行性疾病病例的额叶新皮质尸检样本。这种截短的多肽包含PS1的N端，且在各病例中看起来未发生变化。在2例与PS1基因错义突变相关的早发型病例中，一种PS1免疫反应性蛋白（约49 kd）在额叶皮质中积累。该蛋白的大小与过表达PS1互补DNA的转染细胞中存在的全长PS1蛋白以及一名PS1基因第9外显子缺失的受累个体的淋巴细胞中的全长PS1蛋白相似，这表明PS1基因的突变扰乱了该蛋白的内蛋白水解加工过程。对照脑的免疫组织化学研究显示，PS1主要在神经元中表达，该蛋白定位于胞体和树突状突起。相比之下，在早发型家族性阿尔茨海默病和散发性阿尔茨海默病病例中，PS1在神经病理学部位有明显定位。PS1免疫反应性存在于老年斑的神经炎性成分以及神经原纤维缠结中。PS1免疫反应性在家族性和散发性阿尔茨海默病中的定位表明，该疾病的基因异质性形式共享涉及PS1蛋白的共同病理生理学机制。
