Glutamate, beta-amyloid precursor proteins, and calcium mediated neurofibrillary degeneration.-猫眼课题宝

谷氨酸、β-淀粉样前体蛋白和钙介导的神经原纤维变性。

DOI：

发表时间：

1994

期刊：

Journal of neural transmission. Supplementum

影响因子：

通讯作者：

中科院分区：

文献类型：

作者：

V. Smith;M. Mattson

在这篇文章中，我们提出的证据支持兴奋性毒性，β APP代谢不良，代谢妥协和细胞内钙不稳定的过程中与阿尔茨海默病（AD）相关的神经退行性变之间的相互作用。AD的特征在于在脑的特定区域中存在神经元缠结和含淀粉样蛋白的斑块。似乎有几个过程，有助于与AD相关的神经退行性变。虽然AD与21、19和14号染色体上的基因突变有关，但也有零星形式的AD不涉及已知的基因突变。衰老是AD的主要危险因素。在正常衰老过程中，大脑中可能会发生几种代谢妥协。已知葡萄糖转运和利用减少以及糖皮质激素水平增加均会随着衰老而发生，并可能导致能量供应减少、ATP耗竭、Ca 2+缓冲系统失效、过量谷氨酸释放和谷氨酸受体活化。此外，抗氧化酶的减少和因此自由基的增加也与衰老有关。上述每一种改变都会导致神经元[Ca 2 +]i的增加。升高的钙可以激活钙依赖性蛋白酶，其降解特定的细胞骨架蛋白，以及脂肪酶，其产生自由基，导致膜损伤和可能的细胞死亡。在这篇文章中，我们提供的证据表明，淀粉样β-肽（A β），在AD斑块中积累的物质，加剧兴奋性毒性和代谢的妥协，神经元导致细胞骨架的变化，类似于在AD的神经元缠结中看到的。我们还提供了分泌形式的β-淀粉样前体蛋白（β APP）对兴奋性毒性损伤具有神经保护作用的证据。关于β APP的正常功能和A β毒性机制的最新发现将β APP置于导致AD中神经元变性的变化的中心。

In this article we present evidence supporting the interaction between excitotoxicity, beta APP mismetabolism, metabolic compromise and intracellular calcium destabilization in the process of neurodegeneration associated with Alzheimer's disease (AD). AD is characterized by the presence of neurofibrillary tangles and amyloid-containing plaques in specific regions of the brain. There appear to be several processes which contribute to the neurodegeneration associated with AD. Although AD has been linked to genetic mutations on chromosomes 21, 19 and 14, there are sporadic forms of AD that have no known genetic mutation involved. Aging is the major risk factor for AD. During the course of normal aging several metabolic compromises may occur in the brain. Both decreased glucose transport and utilization, and increased glucocorticoid levels are known to occur with aging and may lead to decreased energy supplies, ATP depletion, failure of Ca2+ buffering systems, excess glutamate release and activation of glutamate receptors. In addition, a reduction in antioxidant enzymes and consequently an increase in free radicals has also been associated with aging. Each of the preceeding alterations would lead to an increase in neuronal [Ca2+]i. Elevated calcium could then activate calcium-dependent proteases which degrade particular cytoskeletal proteins, and lipases which generate free radicals resulting in membrane damage and possible cell death. In this article we provide evidence that amyloid beta-peptide (A beta), the substance which accumulates in AD plaques, exacerbates excitotoxic and metabolic compromises to neurons resulting in changes in the cytoskeleton which resemble those seen in the neurofibrillary tangles of AD. We also provide evidence that secreted forms of beta-amyloid precursor protein (beta APP) are neuroprotective against excitotoxic insults. Recent findings concerning the normal function of beta APP and the mechanism of A beta toxicity place beta APP at the center of changes leading to neuronal degeneration in AD.