Department of Pharmacology, University of Minnesota Minneapolis, MN, USA ; Department of Medicine, University of Minnesota Minneapolis, MN, USA ; Department of Environmental Health Sciences, University of Minnesota Minneapolis, MN, USA.
Front Pharmacol. 2013 May 13;4:59. doi: 10.3389/fphar.2013.00059. eCollection 2013.
It is currently thought that the dementia of Alzheimer's disease is due to the neurotoxicity of the deposits or aggregates of amyloid-β (Aβ) in the extracellular space of the cerebral cortex. This model has been widely criticized because there is a poor correlation between deposits and dementia. Others have questioned whether Aβ is truly neurotoxic. Yet, in spite of these concerns, the search for therapeutic agents has been based on the development of mouse models transfected with mutant genes associated in humans with early onset Alzheimer's disease. A major limitation of these models is that although they exhibit many of the pathological and clinical manifestation of the human disease, the bulk of individuals who develop the dementia of Alzheimer's disease have none of these mutant genes. Furthermore, nine clinical trials of drugs that were effective in transgenic mice failed to show any benefit in patients. Finally, a major unresolved issue with the Aβ model is that since Aβ is produced in everyone, why are deposits only seen in the elderly? This issue must be resolved if we are to understand the etiology of the disease and develop test systems for both diagnosis and drug discovery. Published studies from my laboratory demonstrate that in human cerebrospinal fluid immunoreactive Aβ is only present as a complex with two chaperones, ERp57 and calreticulin and is N-glycosylated. This complex formation is catalyzed by the posttranslational protein processing system of the endoplasmic reticulum (ER). Others have reported that in plaque Aβ is present only as the naked peptide. Together these results suggest that both plaque and dementia are secondary to an age related decline in the capacity of the ER to catalyze protein, posttranslational processing. Since the synaptic membrane proteins necessary for a functioning memory are also processed in the ER, these findings would suggest that the loss of cognition is due to a decline in the capacity of the neuron to produce and maintain functioning synapses. Work from my laboratory and from others further indicate that the components of the ER, posttranslational, protein processing pathway do dramatically decline with age. These data suggest that this decline may be found in all cells and could account not only for the dementia of Alzheimer's disease, but also for many of the other manifestations of the aging process. These observations also suggest that declining ER function has a role in two well-recognized phenomena associated with aging: a loss of mitochondrial function and a decrease in myelin. Finally, based on this paradigm I propose new cellular and animals models for high-throughput screening for drug discovery.
目前认为阿尔茨海默病的痴呆是由于大脑皮层细胞外空间中淀粉样β（Aβ）的神经毒性沉积或聚集所致。该模型受到了广泛的批评，因为沉积与痴呆之间的相关性较差。也有人质疑 Aβ 是否真的具有神经毒性。然而，尽管存在这些担忧，治疗药物的研究仍基于转染与早发性阿尔茨海默病相关的突变基因的小鼠模型。这些模型的一个主要局限性是，尽管它们表现出人类疾病的许多病理和临床表现，但发展为阿尔茨海默病痴呆的大多数个体都没有这些突变基因。此外，九项针对在转基因小鼠中有效的药物的临床试验未能在患者中显示任何益处。最后，Aβ 模型的一个主要未解决的问题是，由于每个人都会产生 Aβ，为什么只有老年人才能看到沉积？如果我们要了解疾病的病因并开发用于诊断和药物发现的测试系统，就必须解决这个问题。我的实验室发表的研究表明，在人类脑脊液中，免疫反应性 Aβ仅以与两种伴侣蛋白 ERp57 和钙网蛋白的复合物形式存在，并且是 N-糖基化的。这种复合物的形成是由内质网（ER）的翻译后蛋白加工系统催化的。其他人报告说，在斑块中，Aβ仅以裸肽的形式存在。这些结果表明，斑块和痴呆都是内质网催化蛋白质翻译后加工能力随年龄相关下降的结果。由于突触膜蛋白也是在 ER 中进行加工的，这些发现表明认知能力的丧失是由于神经元产生和维持功能突触的能力下降所致。我的实验室和其他人的工作进一步表明，内质网的组成部分，翻译后蛋白加工途径，随着年龄的增长而急剧下降。这些数据表明，这种下降可能存在于所有细胞中，不仅可以解释阿尔茨海默病的痴呆，还可以解释衰老过程中的许多其他表现。这些观察结果还表明，内质网功能下降与衰老相关的两个公认现象有关：线粒体功能丧失和髓鞘减少。最后，基于这一范例，我提出了用于高通量药物筛选的新的细胞和动物模型。
