Perturbed endoplasmic reticulum function, synaptic apoptosis and the pathogenesis of Alzheimer's disease
Perturbed endoplasmic reticulum function, synaptic apoptosis and the pathogenesis of Alzheimer's disease
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DOI：
10.1042/bss0670151
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发表时间：
2001-01-01
期刊：
影响因子：
--
通讯作者：
Duan, WZ
中科院分区：
文献类型：
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作者：
Mattson, MP;Gary, DS;Duan, WZ
内质网（ER）似乎是阿尔茨海默病（AD）中导致神经元功能障碍和死亡的改变的焦点。内质网中β -淀粉样蛋白前体蛋白（APP）的异常蛋白水解加工和/或运输可能通过增加β -淀粉样蛋白（A β）的神经毒性形式的水平和降低APP （sAPP α）的神经保护性分泌形式的水平来促进神经元变性。一些AD病例是由编码早老素1 （PS1）的基因突变引起的。当在培养的神经细胞和转基因小鼠中表达时，PS1突变引起内质网钙稳态异常，增强钙对刺激的反应，激活IP3和红嘌呤敏感的内质网钙池。内质网钙调节中断的两个主要后果是改变APP的蛋白水解过程，增加神经元对凋亡和兴奋性毒性的易感性。PS1突变和APP加工异常对突触末端的影响尤其大。突触钙稳态紊乱促进凋亡级联反应的激活，包括Par-4（前列腺凋亡反应-4）的产生、线粒体功能障碍和半胱天冬酶的激活。β 42 （β的42-氨基酸形式）诱导突触和树突的膜脂过氧化，导致膜离子动机atp酶和葡萄糖和谷氨酸转运蛋白受损。这会破坏突触离子和能量的平衡，从而促进突触变性。相反，sAPP激活保护突触免受兴奋性毒性和细胞凋亡的信号通路。在更常见的散发性阿尔茨海默病中，神经退行性级联的起始原因不太明确，但可能涉及氧化应激水平升高和能量代谢受损。在实验模型中，这种改变已被证明会破坏神经元钙稳态，因此可能与早老素和APP突变引发的神经退行性级联反应有关。突触内质网钙稳态紊乱和APP加工随之改变似乎是散发性和家族性AD的关键事件。
Endoplasmic reticulum (ER) appears to be a focal point for alterations that result in neuronal dysfunction and death in Alzheimer's disease (AD). Aberrant proteolytic processing and/or trafficking of the beta -amyloid precursor protein (APP) in ER may promote neuronal degeneration by increasing the levels of the neurotoxic forms of beta -amyloid (A beta) and by decreasing the levels of the neuroprotective secreted form of APP (sAPP alpha).Some cases of AD are caused by mutations in the genes encoding presenilin 1 (PS1). When expressed in cultured neuronal cells and transgenic mice, PS1 mutations cause abnormalities in ER calcium homoeostasis, enhancing the calcium responses to stimuli that activate IP3- and ryanodine-sensitive ER calcium pools. Two major consequences of this disrupted ER calcium regulation are altered proteolytic processing of APP and increased vulnerability of neurons to apoptosis and excitotoxicity. The impact of PS1 mutations and aberrant APP processing is particularly great in synaptic terminals. Perturbed synaptic calcium homoeostasis promotes activation of apoptotic cascades involving production of Par-4 (prostate apoptosis response-4), mitochondrial dysfunction and caspase activation. A beta 42 (the 42-amino-acid form of A beta) induces membrane lipid peroxidation in synapses and dendrites resulting in impairment of membrane ion-motive ATPases and glucose and glutamate transporters. This disrupts synaptic ion and energy homoeostasis thereby promoting synaptic degeneration. In contrast, sAPP alpha activates signalling pathways that protect synapses against excitotoxicity and apoptosis. In the more common sporadic forms of AD, the initiating causes of the neurodegenerative cascade are less well defined, but probably involve increased levels of oxidative stress and impaired energy metabolism. Such alterations have been shown to disrupt neuronal calcium homoeostasis in experimental models, and may therefore feed into the same neurodegenerative cascade initiated by mutations in presenilins and APP. Perturbed synaptic ER calcium homoeostasis and consequent alterations in APP processing appear to be pivotal events in both sporadic and familial forms of AD.