Mattson M P
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230.
Ann N Y Acad Sci. 1994 Dec 15;747:50-76.
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.
阿尔茨海默病（AD）的定义是特定神经元群体的退化以及在受影响的脑区中存在细胞骨架蛋白和淀粉样β肽（Aβ）的不溶性聚集体。阿尔茨海默病似乎并非由单一改变引起，但在某些遗传性AD病例中，特定的基因缺陷可引发该病。在本文中，代谢紊乱、β淀粉样前体蛋白（βAPP）代谢改变以及一种兴奋性毒性形式的神经元损伤被认为是AD发病机制的核心。有人提出假说，神经元Ca2+稳态的破坏是神经元退化的基础，多种与年龄相关和/或基因改变导致了Ca2+稳态的丧失。最近的研究表明，βAPP的分泌形式（APPss）可稳定细胞内游离钙水平（[Ca2+]i）并保护神经元免受兴奋性毒性损伤。相反，由βAPP的不同加工产生的Aβ形成自由基肽和聚集体，使[Ca2+]i不稳定并使神经元易受代谢损伤。βAPP表达增加（如唐氏综合征）或加工改变（如βAPP突变）可能会增加Aβ/APPs比值。AD中神经元的死亡很可能具有兴奋性毒性成分，因为：易损神经元具有高水平的谷氨酸受体；实验诱导的兴奋性毒性表现出与神经原纤维缠结相似的几个特征；并且Aβ可破坏[Ca2+]i稳态并使神经元易受神经原纤维变性的影响。选择性易损性可能源于参与调节[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决定神经元是否能够将[Ca2+]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，最近的研究表明，几种生长因子可稳定[Ca]i并保护神经元免受兴奋性毒性损伤和Aβ毒性。大脑中与年龄相关的变化（如缺血状态、葡萄糖摄取减少和糖皮质激素水平升高）可能会损害正常情况下适应性调节[Ca2+]i的机制。
