FAM222A and amyloid plaque deposition in Alzheimer's Disease

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是老年痴呆的主要病因，以神经系统损害为特征 神经纤维缠结、老年斑以及新皮层和海马中神经元细胞的进行性损失。目前， AD没有有效的治疗方法。不到10%的AD病例是早发性的， 由APP、早老素1（PS1）或早老素2（PS2）的常染色体显性遗传遗传性遗传变化引起，所有 其中，Aβ的过度产生和淀粉样斑块的早期形成是由其引起的。虽然 90%以上的AD病例被称为散发性AD，无家族史，它们具有相似的临床特征。 和病理表型为散发性AD。尽管大量证据表明，Aβ沉积在 脑作为可能的罪魁祸首在AD或相关痴呆的发病机制中起关键作用， 淀粉样蛋白斑形成的病理机制在很大程度上仍然是难以捉摸的。有趣的是，在我们最近的研究中，我们 已经鉴定出一种新的蛋白质聚集蛋白，其特异性地聚集在淀粉样斑块的中心。 聚集蛋白主要在中枢神经系统中表达，并且在患有糖尿病的患者的脑中增加。 AD或淀粉样前体蛋白（APP）转基因小鼠AD。令人兴奋的是，聚集蛋白与 Aβ具有非常高的亲和力，即使在接近生理纳摩尔浓度下也能显著促进Aβ聚集 浓度的聚集蛋白的强制表达导致淀粉样蛋白沉积增加，而 在APP转基因小鼠中，凝集素抑制淀粉样蛋白斑块的形成，进一步表明它是一种抑制淀粉样蛋白斑块形成的基因。 是Aβ聚集形成淀粉样斑块的重要因素。这些令人兴奋和有希望的初步研究 这表明，对聚集蛋白在淀粉样斑块形成中的潜在作用的详细研究， AD是有保证的。使用一种新的转基因小鼠模型，条件性消融聚集蛋白，这项研究将 不仅研究聚集蛋白是否以及如何调节淀粉样斑块形成和疾病进展， 也测试了以Aggregatin为靶点作为治疗AD的新方法的可行性。淀粉样斑块是一种 各种主要神经退行性疾病的突出共同组织病理学特征，包括但不限于 仅限于AD。我们提出的关于聚集蛋白及其与淀粉样斑块的关系的研究将具有非常广泛的意义。 科学和翻译的意义。

PROJECT SUMMARY Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles, senile plaques and a progressive loss of neuronal cells in neocortex and hippocampus. Currently, there is no effective treatment for AD. Less than 10% of AD cases are early onset with only a small fraction caused by autosomal dominantly inherited genetic changes in APP, presenilin 1 (PS1) or presenilin 2 (PS2), all of which are responsible for the overproduction of Aβ and the earlier formation of amyloid plaques. Though more than 90% of AD cases are referred to as sporadic AD without family history, they have the similar clinical and pathologic phenotypes as sporadic AD. Despite a large body of evidence suggests that Aβ deposition in the brain as the likely culprit playing a critical role in the pathogenesis of AD or related dementia, the molecular pathomechanisms of amyloid plaque formation remain largely elusive. Interestingly, in our recent study, we have identified a novel protein Aggregatin specifically accumulated within the centers of amyloid plaques. Aggregatin is predominantly expressed in the central nervous system and increased in brains of patients with AD or amyloid precursor protein (APP) transgenic mice for AD. Excitingly, Aggregatin physically interacts with Aβ with very high affinity, and remarkably facilitates Aβ aggregation even under near-physiologic nanomolar concentrations. Forced expression of Aggregatin resulted in increased amyloid deposition, whereas ablation of Aggregatin suppressed the formation of amyloid plaques in APP transgenic mice, further implying it as an important factor for Aβ aggregating to form amyloid plaques. These exciting and promising preliminary studies suggest that a detailed investigation into the potential role of Aggregatin in the formation of amyloid plaques in AD is warranted. Using a novel transgenic mouse model with conditional ablation of Aggregatin, this study will not only study whether and how Aggregatin regulates amyloid plaque formation and disease progression, but also test the feasibility of targeting Aggregatin as a novel therapeutic approach for AD. Amyloid plaque is a prominent common histopathological feature of in various major neurodegenerative diseases including but not limited to AD. Our proposed studies of Aggregatin and its connection with amyloid plaque will have very broad scientific and translational significance.