Strittmatter W J, Roses A D
Department of Medicine (Neurology), Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 1995 May 23;92(11):4725-7. doi: 10.1073/pnas.92.11.4725.
Inheritance of specific apolipoprotein E (apoE) alleles determines, in large part, the risk and mean age of onset of late-onset familial and sporadic Alzheimer disease. The mechanism by which the apoE isoforms differentially contribute to disease expression is, however, unknown. Isoform-specific differences have been identified in the binding of apoE to the microtubule-associated protein tau, which forms the paired helical filament and neurofibrillary tangles, and to amyloid beta peptide, a major component of the neuritic plaque. These and other isoform-specific interactions of apoE give rise to testable hypotheses for the mechanism(s) of pathogenesis of Alzheimer disease. An unresolved issue of increasing importance is the relationship between the structural pathological lesions and the cellular pathogenesis responsible for the clinical disease phenotype, progressive dementia. The identification of apoE in the cytoplasm of human neurons and the characterization of isoform-specific binding of apoE to the microtubule-associated proteins tau and MAP-2 present the possibility that apoE may affect microtubule function in the Alzheimer brain.
特定载脂蛋白E（apoE）等位基因的遗传在很大程度上决定了晚发性家族性和散发性阿尔茨海默病的发病风险和平均发病年龄。然而，apoE异构体对疾病表现的不同作用机制尚不清楚。已发现apoE与微管相关蛋白tau（其形成双螺旋丝和神经原纤维缠结）以及淀粉样β肽（神经炎性斑块的主要成分）的结合存在异构体特异性差异。apoE的这些以及其他异构体特异性相互作用为阿尔茨海默病的发病机制提出了可检验的假设。一个日益重要的未解决问题是结构病理损伤与导致临床疾病表型（进行性痴呆）的细胞发病机制之间的关系。在人类神经元细胞质中鉴定出apoE以及对apoE与微管相关蛋白tau和MAP - 2的异构体特异性结合进行表征，提示apoE可能影响阿尔茨海默病大脑中的微管功能。
