Wischik C M, Harrington C R, Mukaetova-Ladinska E B, Novak M, Edwards P C, McArthur F K
University of Cambridge Clinical School, Department of Psychiatry, UK.
Ciba Found Symp. 1992;169:268-93; discussion 293-302. doi: 10.1002/9780470514306.ch16.
The neuropathological changes seen in Alzheimer's disease represent an interaction between the ageing process in which normal intellectual function is retained, and changes which are specifically associated with severe cognitive deterioration. Molecular analysis of these changes has tended to emphasize the distinction between neurofibrillary pathology, which is intracellular and highly correlated with cognitive deterioration, and the changes associated with the deposition of extracellular amyloid, which appears to be widespread in normal ageing. Extracellular amyloid deposits consist of fibrils composed of a short 42 amino acid peptide (beta/A4) derived by abnormal proteolysis from a much larger precursor molecule (APP). The recent demonstration of a mutation associated with APP in rare cases with familial dementia, neurofibrillary pathology in the hippocampus and atypical cortical Lewy body pathology raises the possibility that abnormal processing of APP could be linked directly with neurofibrillary pathology. Neurofibrillary tangles and neuritic plaques are sites of dense accumulation of pathological paired helical filaments (PHFs) which are composed in part of an antigenically modified form of the microtubule-associated protein tau. The average brain tissue content of PHFs measured biochemically does not increase in the course of normal ageing but increases 10-fold relative to age-matched controls in patients with Alzheimer's disease. There is also a substantial (three-fold) disease-related decline in normal soluble tau protein relative to age-matched controls. This intracellular redistribution of a protein essential for microtubule stability in cortico-cortical association circuits may play an important part in the molecular pathogenesis of dementia in Alzheimer's disease. The role of abnormal proteolysis of APP in this process remains to be elucidated. Immunohistochemical studies on renal dialysis cases have failed to detect evidence of neurofibrillary pathology related to aluminium accumulation in brain tissue. Nevertheless it needs to be seen whether more sensitive biochemical assays of neurofibrillary pathology can demonstrate evidence of an association with aluminium.
阿尔茨海默病中所见的神经病理学变化代表了正常智力功能得以保留的衰老过程与那些与严重认知衰退具体相关的变化之间的相互作用。对这些变化的分子分析倾向于强调神经原纤维病理学（其为细胞内病变且与认知衰退高度相关）与细胞外淀粉样蛋白沉积相关变化（在正常衰老过程中似乎广泛存在）之间的区别。细胞外淀粉样蛋白沉积物由纤维组成，这些纤维由一种短的42个氨基酸的肽（β/A4）构成，该肽是通过异常蛋白水解从一个大得多的前体分子（APP）衍生而来。最近在罕见的家族性痴呆病例中发现与APP相关的突变、海马体中的神经原纤维病理学以及非典型皮质路易体病理学，这增加了APP异常加工可能与神经原纤维病理学直接相关的可能性。神经原纤维缠结和神经炎性斑块是病理性双螺旋丝（PHF）密集聚集的部位，PHF部分由微管相关蛋白tau的抗原修饰形式组成。通过生化方法测量，正常衰老过程中PHF的平均脑组织含量不会增加，但在阿尔茨海默病患者中相对于年龄匹配的对照组增加了10倍。相对于年龄匹配的对照组，正常可溶性tau蛋白也有与疾病相关的大幅（三倍）下降。这种对皮质 - 皮质联合回路中微管稳定性至关重要的蛋白质的细胞内重新分布可能在阿尔茨海默病痴呆的分子发病机制中起重要作用。APP异常蛋白水解在此过程中的作用仍有待阐明。对肾透析病例的免疫组织化学研究未能检测到与脑组织中铝积累相关的神经原纤维病理学证据。然而，需要观察更敏感的神经原纤维病理学生化检测是否能证明与铝有关联的证据。
