The Significance of Glucose Turnover in the Brain in the Pathogenetic Mechanisms of Alzheimer's Disease
The Significance of Glucose Turnover in the Brain in the Pathogenetic Mechanisms of Alzheimer's Disease
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大脑葡萄糖周转在阿尔茨海默病发病机制中的意义
DOI：
10.1515/revneuro.1996.7.1.1
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发表时间：
1996
影响因子：
4.1
通讯作者：
C. Bertoni–Freddari
中科院分区：
文献类型：
--
作者：
W. Meier;C. Bertoni–Freddari
本文介绍了阿尔茨海默病（AD）的发病机制和病理生理学的全面调查。两种机制在退行性痴呆脑疾病的发展中具有重要的病因学意义：1。线粒体基因组中由自由基引起的病变。原发性退行性AD的特征在于在线粒体DNA内获得由自由基产生的随机损伤的趋势。这些病变的后果是葡萄糖周转减少和氧化磷酸化下降。假设21号染色体上的点突变增加了线粒体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。这些神经递质增加CA（+2）流入神经细胞，并显着降低能量产生。从发病的角度来看，AD的特征在于脑中葡萄糖周转的减少。AD的进展可以通过F18-脱氧葡萄糖PET研究来监测。该技术还允许识别易于发展为AD的患者。认知缺陷的实际发展是一种阈值现象，如果海马或颞顶皮层中的葡萄糖周转率下降到年龄匹配对照水平的约40%的临界水平以下，则会发生这种现象。AD中的低葡萄糖周转率通过减少AcCoA的合成而引起胆碱能缺陷，AcCoA被胆碱乙酰转移酶用于胆碱乙酰化为乙酰胆碱。葡萄糖周转的减少也减少氧化磷酸化。由此产生的ATP减少通过激活蛋白激酶40 erk触发tau蛋白的过度磷酸化。过度磷酸化导致成对螺旋丝的发育。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的减少引起的，因为β淀粉样蛋白前体蛋白在缺乏足够量的ATP的情况下不会插入神经细胞的膜中。这导致完整的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的淀粉样变性。
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.
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DOI：
10.1073/pnas.90.5.1977
发表时间：
1993-03-01
影响因子：
11.1
作者：
STRITTMATTER, WJ;SAUNDERS, AM;ROSES, AD
通讯作者：
ROSES, AD
DOI：
10.1073/pnas.88.16.7247
发表时间：
1991-08-01
影响因子：
11.1
作者：
KOWALL, NW;BEAL, MF;YANKNER, BA
通讯作者：
YANKNER, BA
影响因子：
56.9
作者：
BUSH, AI;PETTINGELL, WH;TANZI, RE
通讯作者：
TANZI, RE
DOI：
10.1001/jama.1995.03520360056039
发表时间：
1995-03
期刊：
JAMA
影响因子：
--
作者：
G. Small;J. Mazziotta;M. Collins;L. Baxter;M. Phelps;M. Mandelkern;A. Kaplan;A. la Rue;C. Adamson;L. Chang
通讯作者：
G. Small;J. Mazziotta;M. Collins;L. Baxter;M. Phelps;M. Mandelkern;A. Kaplan;A. la Rue;C. Adamson;L. Chang
影响因子：
56.9
作者：
SELKOE, DJ;BELL, DS;CORK, LC
通讯作者：
CORK, LC