Meier-Ruge W A, Bertoni-Freddari C
Division of Gerontological Brain Research, Department of Pathology, University Medical School, Basel, Switzerland.
Gerontology. 1999 Sep-Oct;45(5):289-97. doi: 10.1159/000022104.
The recent, magnificent results of molecular biology concerning beta-amyloid (betaA) metabolism in early onset Alzheimer's disease (AD) have generated a series of new findings and, in turn, a new etiological concept. Attention on the early events in the pathogenesis of AD has been shifted from the chromosomal abnormalities in the nucleus of nerve cells onto genetic changes in the mitochondrial genome. This offers a new pathogenetic approach which also opens new pharmacological challenges particularly for the episodic forms of AD.
Alterations occurring at the mitochondrial genome result in major consequences of oxidative phosphorylation and, if a specific threshold is exceeded, they may constitute important causative events in the apoptosis of selected nerve cells. The fact that the main source of mitochondrial metabolism is its glucose turnover allows monitoring brain changes in glucose metabolism by 18F-2 deoxyglucose positron emission tomography. In the demented brain, a low glucose turnover causes a cholinergic deficit by decreasing the synthetic rate of acetyl coenzyme A (AcCoA). AcCoA represents the key substrate for the acetylation of choline to acetylcholine by choline acetyltransferase. The consistent energy need for AcCoA synthesis appears obvious when considering that 1 molecule of glucose generates just 2 molecules of AcCoA, but 38 molecules of ATP. In the brain, AcCoA is exclusively synthesized in the glycolitic pathway. Generation of betaA is increased if the synthetic rate of ATP drops below a critical threshold: under these conditions, the betaA precursor protein (betaAPP) is inserted only in part into synaptic membranes which have the highest betaAPP turnover. In conditions of short ATP supply, betaAPP is not split at the beta region by an ATP-activated protease and this results in a substantial increase in uncleaved betaA molecules.
Peroxidative alterations in mitochondrial DNA are of importance in degenerative diseases of postmitotic tissues, particularly in degenerative diseases. This offers a new pharmacological approach for the treatment of AD. Neurotrophic factors and estrogen seem to be the first pharmacological leads.
分子生物学在早发性阿尔茨海默病（AD）β-淀粉样蛋白（βA）代谢方面取得的近期显著成果产生了一系列新发现，进而形成了一种新的病因学概念。对AD发病机制早期事件的关注已从神经细胞核中的染色体异常转移到线粒体基因组的遗传变化上。这提供了一种新的发病机制研究方法，也带来了新的药理学挑战，尤其是对发作性AD形式而言。
线粒体基因组发生的改变会导致氧化磷酸化产生重大后果，并且如果超过特定阈值，可能构成特定神经细胞凋亡的重要致病事件。线粒体代谢的主要来源是其葡萄糖周转这一事实使得通过18F - 2脱氧葡萄糖正电子发射断层扫描来监测大脑葡萄糖代谢变化成为可能。在痴呆大脑中，低葡萄糖周转通过降低乙酰辅酶A（AcCoA）的合成速率导致胆碱能缺陷。AcCoA是胆碱乙酰转移酶将胆碱乙酰化为乙酰胆碱的关键底物。考虑到1分子葡萄糖仅产生2分子AcCoA，但能产生38分子ATP，AcCoA合成所需的持续能量需求就显得很明显了。在大脑中，AcCoA仅在糖酵解途径中合成。如果ATP合成速率降至临界阈值以下，βA的生成会增加：在这些情况下，βA前体蛋白（βAPP）仅部分插入βAPP周转最高的突触膜中。在ATP供应短缺的情况下，βAPP不会被ATP激活的蛋白酶在β区域切割，这导致未切割的βA分子大量增加。
线粒体DNA的过氧化改变在有丝分裂后组织的退行性疾病中很重要，尤其是在退行性疾病中。这为AD的治疗提供了一种新的药理学方法。神经营养因子和雌激素似乎是首批药理学线索。
