Calcium and Neuronal Injury in Alzheimer's Disease-猫眼课题宝

阿尔茨海默病中的钙和神经元损伤

DOI：

10.1111/j.1749-6632.1994.tb44401.x

发表时间：

1994

期刊：

Annals of the New York Academy of Sciences

影响因子：

5.2

通讯作者：

中科院分区：

综合性期刊3区

文献类型：

作者：

M. Mattson

阿尔茨海默病（AD）的定义是特定神经元群体的变性以及受影响脑区域内细胞骨架蛋白和淀粉样β-肽（A β）的不溶性聚集体的存在。阿尔茨海默氏病似乎不是由单一的改变引起的，但在某些遗传性AD病例中，特定的遗传缺陷可能会导致疾病。在这篇文章中，代谢妥协，β-淀粉样前体蛋白（β APP）的代谢改变，和神经元损伤的兴奋毒性形式被认为是AD发病机制的核心。提出了神经元钙稳态不稳定是神经元变性的基础，多种年龄相关和/或遗传改变导致钙稳态丧失的假设。最近的研究表明，分泌形式的β APP（APPss）稳定细胞内游离钙水平（[Ca 2 +]i）并保护神经元免受兴奋性毒性损伤。相反，由β APP的替代加工产生的A β形成自由基肽和聚集体，其使[Ca 2 +]i不稳定并使神经元易受代谢损伤。β APP的表达增加（例如唐氏综合征）或加工改变（例如β APP突变）可能会增加A β/APP比值。AD中神经元的死亡很可能具有兴奋性毒性成分，因为：脆弱的神经元具有高水平的谷氨酸受体;实验诱导的兴奋性毒性显示出与神经元缠结相似的几个特征; A β可以破坏[Ca 2 +]i稳态并使神经元易于神经元变性。选择性脆弱性可能是由于参与调节[Ca+]i的蛋白质表达的细胞类型特异性差异。此外，许多细胞间信号参与确定神经元是否能够将[Ca 2 +]i维持在有利于细胞存活和适应性可塑性的浓度范围内。在这方面，最近显示，几种生长因子可以稳定[Ca]i并保护神经元免受兴奋性毒性损伤和A β毒性。脑内钙相关变化（如缺血性疾病、葡萄糖摄取减少和糖皮质激素水平升高）可能会损害正常自适应调节[Ca 2 +]i的机制。

Alzheimer's disease (AD) is defined by degeneration of specific populations of neurons and the presence of insoluble aggregates of cytoskeletal proteins and amyloid beta-peptide (A beta) within affected brain regions. Alzheimer's disease does not appear to result from a single alteration, but in some cases of inherited AD a specific genetic defect can precipitate the disease. In this article, metabolic compromise, altered metabolism of the beta-amyloid precursor protein (beta APP), and an excitotoxic form of neuronal injury are considered central to the pathogenesis AD. The hypothesis is forwarded that destabilization of neuronal Ca2+ homeostasis underlies neuronal degeneration and that multiple age-associated and/or genetic alterations contribute to the loss of Ca2+ homeostasis. Recent studies showed that the secreted forms of beta APP (APPss) stabilize intracellular free calcium levels ([Ca2+]i) and protect neurons against excitotoxic insults. In contrast, A beta which arises from alternative processing of beta APP forms free radical peptides and aggregates that destabilize [Ca2+]i and make neurons vulnerable to metabolic insults. Increased expression (eg, Down's syndrome) or altered processing (eg, beta APP mutations) of beta APP may increase the A beta/APPs ratio. The death of neurons in AD most likely has an excitotoxic component because: the vulnerable neurons possess high levels of glutamate receptors; experimentally induced excitotoxicity shows several features similar to those of neurofibrillary tangles; and A beta can destabilize [Ca2+]i homeostasis and render neurons vulnerable to neurofibrillary degeneration. Selective vulnerability may result from cell type-specific differences in expression of proteins involved in regulating [Ca+]i. In addition, many intercellular signals are involved in determining whether a neuron is able to maintain [Ca2+]i within a range of concentrations conducive to cell survival and adaptive plasticity. In this regard, it was recently shown that several growth factors can stabilize [Ca]i and protect neurons against excitotoxic injury and A beta toxicity. Age-related changes in the brain (eg, ischemic conditions, reduced glucose uptake, and increased glucocorticoid levels) may compromise the mechanisms that normally regulate [Ca2+]i adaptively.