FAM222A and amyloid plaque deposition in Alzheimer's Disease

项目总结 阿尔茨海默病(AD)是老年人痴呆的主要原因，以神经原纤维为特征 新皮质和海马区神经元细胞进行性丢失。目前， 目前尚无治疗阿尔茨海默病的有效方法。不到10%的AD病例是早发的，只有一小部分 由常染色体显性遗传性APP、早老素1(PS1)或早老素2(PS2)基因改变引起 其中Aβ的过度生产和淀粉样斑块的早期形成是主要原因。尽管 90%以上的AD患者为散发性AD，无家族史，临床表现相似 病理表型为散发性AD。尽管有大量证据表明β在 大脑作为可能的罪魁祸首在AD或相关痴呆的发病机制中发挥关键作用，分子 淀粉样斑块形成的病理机制在很大程度上仍然难以捉摸。有趣的是，在我们最近的研究中，我们 已经确定了一种新的蛋白质Aggregatin，它专门积聚在淀粉样斑块的中心。 Aggregatin主要在中枢神经系统表达，在慢性阻塞性肺疾病患者脑中表达增加 AD或淀粉样前体蛋白(APP)转基因小鼠治疗AD。令人兴奋的是，Aggregatin与 一种亲和力非常高的β，即使在近生理的纳分子条件下也能显著促进β的聚集 浓度。强迫表达Aggregatin导致淀粉样蛋白沉积增加，而消融Aggregatin Aggregatin抑制APP转基因小鼠淀粉样斑块的形成，进一步暗示它是一种 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 建议对Aggregatin在淀粉样斑块形成中的潜在作用进行详细研究 广告是有根据的。使用一种新的转基因小鼠模型，条件消融Aggregatin，本研究将 不仅研究Aggregatin是否以及如何调节淀粉样斑块的形成和疾病进展，而且 同时测试靶向Aggregatin作为治疗AD的一种新方法的可行性。淀粉样斑块是一种 各种主要神经退行性疾病的显著共同组织病理学特征，包括但不是 仅限于AD。我们提出的关于聚集素及其与淀粉样斑块的联系的研究将具有非常广泛的意义。 科学意义和翻译意义。

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.