Meier-Ruge W, Bertoni-Freddari C
Department of Pathology, University Medical School Basel, Switzerland.
Rev Neurosci. 1996 Jan-Mar;7(1):1-19. doi: 10.1515/revneuro.1996.7.1.1.
This paper presents a comprehensive survey of the pathogenesis and pathophysiology of Alzheimer's disease (AD). Two mechanisms are of etiological importance in the development of a degenerative dementing brain disease: 1. Lesions in the mitochondrial genome that are caused by free radicals. Primary degenerative AD is characterized by a tendency to acquire random lesions within mitochondrial DNA that are produced by free radicals. The consequence of these lesions is a decrease in glucose turnover and a decline in oxidative phosphorylation. Point mutations on chromosome 21 are hypothesized to increase the susceptibility of mitochondrial DNA to lesions created by free radicals. 2. Ischemic brain lesions as well as traumatic brain damage cause an increase in the release of excitotoxic amino acids (glutamate, aspartate, etc.). These neurotransmitters increase CA(+2) influx into the nerve cell and significantly lower energy production. From a pathogenetic point of view, AD is characterized by a decrease in glucose turnover in the brain. The progression of AD can be monitored by F18- deoxyglucose PET studies. This technique also allows the recognition of patients who are prone to develop AD. The actual development of a cognitive deficit is a threshold phenomenon that occurs if glucose turnover in the hippocampus or temporoparietal cortex drops below a critical level of about 40% of the level of age-matched controls. The low glucose turnover in AD causes a cholinergic deficit by decreasing the synthesis of AcCoA, which is used by choline acetyltransferase in the acetylation of choline to acetylcholine. The decrease in glucose turnover also reduces oxidative phosphorylation. The resulting decrease in ATP triggers the hyperphosphorylation of tau protein by activating protein kinase 40erk. The hyperphosphorylation leads to the development of paired helical filaments. The generation of beta amyloid and the loss of neuronal synapses are also caused by a decrease in oxidative phosphorylation, since beta amyloid precursor proteins are not inserted into the membranes of nerve cells in the absence of a sufficient amount of ATP. This results in the generation of intact beta amyloid molecules and leads to amyloidosis in the brains of patients with Alzheimer's disease.
本文全面综述了阿尔茨海默病（AD）的发病机制和病理生理学。在退行性痴呆性脑病的发展过程中，有两种机制具有病因学重要性：1. 自由基导致的线粒体基因组损伤。原发性退行性AD的特征是线粒体DNA内倾向于出现由自由基产生的随机损伤。这些损伤的后果是葡萄糖代谢率降低和氧化磷酸化下降。据推测，21号染色体上的点突变会增加线粒体DNA对自由基造成的损伤的易感性。2. 缺血性脑损伤以及创伤性脑损伤会导致兴奋性毒性氨基酸（谷氨酸、天冬氨酸等）释放增加。这些神经递质会增加钙离子流入神经细胞，并显著降低能量产生。从发病机制的角度来看，AD的特征是大脑中葡萄糖代谢率降低。AD的进展可以通过F18-脱氧葡萄糖PET研究进行监测。该技术还能识别出易患AD的患者。认知缺陷的实际出现是一种阈值现象，当海马体或颞顶叶皮质的葡萄糖代谢率降至低于年龄匹配对照组水平约40%的临界水平时就会发生。AD中葡萄糖代谢率低会通过减少乙酰辅酶A的合成导致胆碱能缺陷，而胆碱乙酰转移酶在将胆碱乙酰化为乙酰胆碱的过程中会用到乙酰辅酶A。葡萄糖代谢率的降低还会减少氧化磷酸化。由此导致的ATP减少会通过激活蛋白激酶40erk触发tau蛋白的过度磷酸化。过度磷酸化会导致双螺旋丝的形成。β淀粉样蛋白的产生和神经元突触的丧失也是由氧化磷酸化减少引起的，因为在没有足够量ATP的情况下，β淀粉样前体蛋白无法插入神经细胞膜。这会导致完整的β淀粉样蛋白分子的产生，并导致阿尔茨海默病患者大脑中出现淀粉样变性。
