Trem2-mediated microglia-neuronal axis in Alzheimer disease pathogenesis

Trem2介导的小胶质细胞神经元轴在阿尔茨海默病发病机制中的作用

基本信息

批准号：
10817330
负责人：
LUCIANO D'ADAMIO
金额：
$ 78.25万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10817330
关键词：
Abeta clearance Adult Age-associated memory impairment Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acids Amyloid Beta A4 Precursor Protein Amyloid beta-Protein Animal Model Animals Behavioral Binding Brain Brain Pathology Caregivers Cells Cerebrum Cognitive Consensus Dementia Deposition Disease Elderly Equilibrium Family Gene Mutation Genetic Human Impaired cognition Impairment Individual Intelligence Knock-in Learning Link Longevity Mediating Memory Microglia Microtubules Modeling Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Organism Pathogenesis Pathogenicity Pathologic Pathologic Processes Pathway interactions Patients Peptides Pharmaceutical Preparations Physiological Processes Population Prevalence Protein Isoforms Proteolytic Processing Rattus Research Risk Rodent Role Senile Plaques Signal Transduction Societies Spices Synaptic Transmission TNF gene TREM2 gene Tauopathies Testing Therapeutic Transgenic Model Transgenic Organisms Treatment Efficacy Variant amyloid precursor protein processing autosomal dominant mutation beta secretase drug testing early onset familial Alzheimer disease gamma secretase genetic variant hyperphosphorylated tau insight model organism neuroinflammation overexpression presenilin-1 presenilin-2 prevent protective allele tau Proteins tau expression therapeutic evaluation therapeutic target therapeutically effective transcriptome transcriptomics

项目摘要

Abstract Alzheimer’s Disease (AD) is the most common cause of ageing-dependent dementia in the world and is associated with cerebral amyloid plaques, mostly composed of Aβ peptides, and intraneuronal neurofibrillary tangles, mostly composed by hyperphosphorylated tau. The impacts of AD on patients, families, caregivers and society are shattering. Regrettably, AD-modifying drugs are unavailable underscoring the scant understanding of AD pathogenesis. ~5% of AD cases have early onset (<65 yo) and are due to Familial autosomal dominant mutations in APP, PSEN1 and PSEN2 (FAD); ~95% of cases are sporadic with late onset (>65 yo, SAD). Yet, commonly used animal organisms model FAD. This may be an issue if FAD and SAD present significant pathogenic differences. If so, therapeutics effective in FAD animals may have limited efficacy in SAD patients. Thus, models that reproduce the pathogenesis of SAD are needed to identify therapeutic targets and test SAD-modifying therapeutics. Variants of the microglia gene TREM2 increase the risk of SAD by 3 fold. To gain insights into the pathogenic mechanisms of SAD, we generated rats carrying the p.R47H pathogenic variant in the rat Trem2 gene (Trem2R47H). Rat and human APP differ by 3 amino acids in the Aβ region. These differences may be crucial in this model organism because: 1) human Aβ possesses higher propensity to form toxic species as compared to rodent Aβ; 2) the pathogenic role of the p.R47H TREM2 variant may be linked to deficits in microglia-mediated human Aβ clearance. To overcome this issue, we humanized the rat Aβ sequence (Apph allele); thus, our rat models produce human Aβ from the endogenous rat App gene. We choose a knock in (KI) approach rather than the more common transgenic overexpression approach because KI models make no preconceived assumption about pathogenic mechanisms, except the unbiased genetic one. In contrast, transgenic models, which produce high levels of Ab and can readily deposit amyloid plaques, are based on the hypothesis that plaques and/or other forms of toxic Ab have a central pathogenic role. We propose to dissect pathogenic mechanisms triggered by the p.R47H pathogenic variant using these KI rat models. We will also study the impact of Trem2R47H on the pathological processes triggered by the Apps and Psen1LF FAD mutations. We will analyze microglia function, cell-to-cell transcriptomic changes in the brain, APP processing, brain pathology, neuro-inflammation and neurodegeneration, synaptic transmission/plasticity, learning & memory. Dissecting pathogenic pathways set off by the Trem2R47H variant may pave the way to therapeutic approaches that can prevent/delay sporadic AD.

摘要阿尔茨海默氏病（AD）是依赖衰老的最常见原因世界上的痴呆症，与脑淀粉样斑块有关，主要由Aβ组成肽和神经元神经原纤维缠结，主要由高磷酸化的 tau。广告对患者，家庭，照顾者和社会的影响正在破坏。遗憾的是， AD修改药物无法强调对AD发病机理的了解很少。〜5％的AD病例患有早期发作（<65 YO），是由于家族性常染色体显性剂 APP，PSEN1和PSEN2（FAD）中的突变；〜95％的病例是零星发病的零星（> 65 哟，悲伤）。然而，常用的动物生物模型时尚。如果FAD和 SAD目前的致病差异很大。如果是这样，在FAD动物中有效的治疗可能 SAD患者的效率有限。那是重现SAD发病机理的模型是需要识别治疗靶标并测试SAD修改疗法。变体小胶质细胞基因trem2增加了SAD的风险3倍。为了洞悉致病性 SAD的机制，我们产生了大鼠携带P.R47H致病变体的大鼠 TREM2基因（TREM2R47H）。大鼠和人类应用程序在Aβ区的3个氨基酸差异。这些在该模型生物体中，差异可能至关重要，因为：1）人Aβ具有更高的与啮齿动物Aβ相比，形成有毒物种的倾向； 2）P.R47H的致病作用 TREM2变体可以与小胶质细胞介导的人Aβ清除率定义有关。到克服了这个问题，我们将大鼠Aβ序列（APPH等位基因）人性化。因此，我们的老鼠模型从内源性大鼠应用基因产生人Aβ。我们选择敲门方法（ki）方法而不是更常见的转基因过表达方法，因为Ki模型没有关于致病机制的先入为主的假设，除了公正的遗传机制。对比，转基因模型，产生高水平的AB，可以容易地沉积淀粉样蛋白斑块是基于以下假设：斑块和/或其他形式的有毒AB具有中央致病作用。我们建议剖析P.R47H触发的致病机制使用这些Ki大鼠模型的致病变体。我们还将研究trem2r47h对应用程序和PSEN1LF FAD突变触发的病理过程。我们将分析小胶质细胞功能，细胞间的大脑转录组变化，应用程序处理，大脑病理学，神经炎症和神经变性，突触传播/可塑性，学习＆记忆。解剖由TREM2R47H变体设定的致病途径可能会铺平道路可以预防/延迟零星广告的治疗方法。