Trem2-mediated microglia-neuronal axis in Alzheimer disease pathogenesis

摘要阿尔茨海默病(AD)是导致衰老依赖的最常见原因 世界上的痴呆症，与大脑淀粉样斑块有关，主要由Aβ组成 多肽和神经元内神经原纤维缠结，主要由过度磷酸化组成 陶先生。阿尔茨海默病对患者、家庭、照顾者和社会的影响是巨大的。遗憾的是， AD修饰药物缺乏，突显了人们对AD发病机制的了解还很少。 约5%的AD患者起病早(65岁)，并由家族性常染色体显性遗传引起 APP、PSEN1和PSEN2突变(FAD)；~95%的病例是散发性的，起病晚(&gt；65 哟，萨德)。然而，常用的动物生物体模型时髦。这可能是一个问题，如果时尚和 SAD表现出明显的病原学差异。如果是这样的话，对时尚动物有效的疗法可能会 对SAD患者的疗效有限。因此，再现SAD发病机制的模型有 需要确定治疗目标和测试SAD修饰疗法。的变种 小胶质细胞基因TREM2使SAD的风险增加3倍。为了深入了解致病因素 SAD的机制，我们建立了携带P.R47H致病变异体的大鼠 TREM2基因(Trem2R47H)。大鼠APP与人类APP在Aβ区有3个氨基酸差异。这些 在这种模式生物中，差异可能是至关重要的，因为：1)人类Aβ拥有更高的 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变异可能与小胶质细胞介导的人类Aβ清除缺陷有关。至 克服了这个问题，我们人源化了大鼠Aβ序列(APPH等位基因)；因此，我们的大鼠模型 从内源性大鼠APP基因产生人Aβ。我们选择了敲门(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，除了无偏见的遗传机制。在……里面 相比之下，产生高水平抗体并容易沉积淀粉样蛋白的转基因模型 斑块是基于这样的假设：斑块和/或其他形式的毒性抗体具有中枢 致病作用。我们建议对P.R47H引发的致病机制进行剖析 使用这些KI大鼠模型的致病变异。我们还将研究Trem2R47H对 Apps和Psen1LF Fad突变引发的病理过程。我们将分析 小胶质细胞功能，脑内细胞间转录变化，APP处理，脑 病理学、神经炎症和神经退行性变、突触传递/可塑性、学习 &记忆。解剖Trem2R47H变异体引发的致病途径可能为 涉及可以预防/延缓散发性AD的治疗方法。

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.