Brion J P
Laboratory of Pathology and Electron Microscopy, Faculté de Médecine, Université Libre de Bruxelles, Belgium.
Acta Clin Belg. 1996;51(2):80-90. doi: 10.1080/17843286.1996.11718490.
Significant developments in our understanding of the pathophysiology of Alzheimer's disease have been obtained in the recent years. Diagnostic criteria, based on clinical data, have been proposed and have been validated by clinico-pathological correlations. Some neuroimaging techniques and laboratory tests (e.g. dosage in the cerebrospinal fluid) are promising diagnostic avenues. Genetic mutations associated with familial cases of the disease have been identified and the involved genes localized on chromosome 1, 14 or 21. The apolipoprotein E genotype has been discovered to affect the risk of developing the disease, i.e. homozygotes for the apolipoprotein E4 allele are much more prone to develop Alzheimer's disease The definitive diagnosis of the disease still relies on the demonstration of characteristic neuropathological lesions, i.e. neurofibrillary tangles and senile plaques, whose numbers are correlated with the severity of the dementia. Other lesions include neuronal and synaptic loss, amyloid angiopathy, and severe decrease in the level of cortical acetylcholine. Neurofibrillary tangles have been found to be composed of the microtubule-associated protein tau, in highly phosphorylated state. The accumulation of these phosphorylated tau proteins is thought to be associated to disturbances of intracellular transport of molecules and organelles in affected neurones, leading to cell dysfunction and death. An inbalance in the activities of selected protein kinases and phosphatases is also thought to generate these highly phosphorylated tau species. The major component of senile plaques is the A4/beta amyloid peptide, generated by proteolysis of the amyloid peptide precursor, a transmembrane protein. When aggregated into amyloid fibrils, the A4/beta amyloid peptide is thought to be neurotoxic. An abnormal metabolism of the amyloid peptide precursor is often considered as a central physiopathological mechanism of the disease. Although many pharmacological treatments of the disease have been investigated, they have not yet led to sustained and major clinical improvements.
近年来，我们对阿尔茨海默病病理生理学的认识取得了重大进展。基于临床数据的诊断标准已被提出，并通过临床病理相关性得到验证。一些神经影像学技术和实验室检查（如脑脊液检测）是很有前景的诊断途径。与该疾病家族性病例相关的基因突变已被识别，相关基因定位于1号、14号或21号染色体上。已发现载脂蛋白E基因型会影响患该病的风险，即载脂蛋白E4等位基因的纯合子更易患阿尔茨海默病。该疾病的确诊仍依赖于特征性神经病理病变的证实，即神经原纤维缠结和老年斑，其数量与痴呆的严重程度相关。其他病变包括神经元和突触丧失、淀粉样血管病以及皮质乙酰胆碱水平严重降低。已发现神经原纤维缠结由高度磷酸化状态的微管相关蛋白tau组成。这些磷酸化tau蛋白的积累被认为与受影响神经元内分子和细胞器的细胞内运输紊乱有关，导致细胞功能障碍和死亡。还认为某些蛋白激酶和磷酸酶活性的失衡会产生这些高度磷酸化的tau蛋白。老年斑的主要成分是A4/β淀粉样肽，它由跨膜蛋白淀粉样肽前体经蛋白水解产生。当聚集成淀粉样纤维时，A4/β淀粉样肽被认为具有神经毒性。淀粉样肽前体的异常代谢通常被视为该疾病的核心病理生理机制。尽管已经对该疾病的许多药物治疗进行了研究，但尚未带来持续且显著的临床改善。
