Evaluating Mechanisms Underlying Resistance in Alzheimer’s Disease

项目摘要 阿尔茨海默病（AD）是最普遍的神经退行性疾病，影响超过50 全球百万人。年龄和遗传变异可以使个体处于高风险状态， 发展中的AD，但一个独特的子集的人在较高的风险抵抗病理和不发展 疾病最近的报道暗示胶质淋巴系统和淀粉体（CA）在糖尿病中的作用。 清除大脑废物淀粉体聚集细胞碎片，如蛋白质和 将它们挤出到CSF中，在那里它们行进到颈部淋巴结并被吞噬。 CA的正常功能可能在AD抵抗中起作用，并且可能受年龄的影响， 病理程度和遗传风险。了解大脑对有毒蛋白质的先天反应 聚集体对于更深入地理解AD病理学的发展至关重要， 潜在地识别疾病生物标志物。在这里，我们调查CA是否有助于 通过定量CA的位置和数量在海马中的后AD病理的抗性， 死亡AD和对照组大脑为了评估耐药性的潜在机制，我们将目标对准了 回答以下问题：1）CA对细胞内pTau的清除是否与以下相关： 对AD病理学的抵抗力？2)在发展AD相关tau病理学的个体中，做CA， 遗传学和血管病理学影响tau蛋白积聚的密度和分布， 穿过海马体研究这些问题将有助于确定和量化新的贡献 在风险升高的情况下对AD的耐药性。本研究金项目提案提供了 有机会在计算神经科学和遗传流行病学培训。

PROJECT SUMMARY Alzheimer disease (AD) is the most prevalent neurodegenerative disorder, affecting over 50 million people worldwide. Age and genetic variation can place individuals at high risk for developing AD, yet a unique subset of people at higher risk resist pathology and do not develop disease. Recent reports implicate the glymphatic system and corpora amylacea (CA) in the clearance of brain waste products. Corpora Amylacea amass cellular debris such as proteins and extrude them into the CSF where they travel to the cervical lymph nodes and are phagocytosed. The proper functioning of CA may play a role in AD resistance, and might be influenced by age, degree of pathology, and genetic risk. Understanding the brain’s innate response to toxic protein aggregates is essential for a deeper understanding of the development of AD pathology and potentially identifying disease biomarkers. Here we investigate whether CA contribute to resistance to AD pathology by quantifying CA location and number in the hippocampus of post- mortem AD and control brains. To evaluate the mechanisms underlying resistance we aim the answer the following questions: 1) Is clearance of intracellular pTau by CA associated with resistance to AD pathology? 2) In individuals who develop AD-related tau pathology, do CA, genetics, and vascular pathology influence the density of tau accumulation and the distribution across the hippocampus? Answering these questions will identify and quantify novel contributions to resistance of AD in the presence of elevated risk. This fellowship project proposal offers the opportunity to train in computational neuroscience and genetic epidemiology.