Molecular pathobiology of soluble TREM2 in Alzheimer's disease

项目总结 阿尔茨海默病(AD)是世界范围内最突出的神经退行性疾病，在病理上是 以Aβ斑块和tau缠结为特征。越来越多的证据表明，小胶质细胞受体 TREM2可在Aβ和tau病理中发挥作用。TREM2被ADAM蛋白水解酶降解 产生可溶性TREM2(STREM2)。尽管脑脊液中sTREM2水平显著升高 (CSF)在AD发病的早期阶段，与tau和pho-tau一起，关于 在我们之前的R01研究之前，sTREM2的功能。我们的团队和其他人确定了TREM2是一个潜在的 一种β受体，它介导小胶质细胞对Aβ寡聚体的激活(赵等人，2018年)。而且，我们的 先前的MPI研究小组发现，腺病毒介导的sTREM2表达可以减少Aβ的积累，并促进 小胶质细胞激活(钟等人，2019年)。有趣的是，最近发现TREM2裂解位点发生在 H157，其中AD相关的H157Y TREM2变体增强了TREM2依赖于ADAM的TREM2切割。 因此，我们将H157Y突变整合到小鼠的TREM2基因座中，并表征了H157Y的作用 5xFAD背景下的TREM2。我们发现，与sTREM2表达类似，H157Y TREM2减少了Aβ斑块 负载和增强的Aβ清除，表明与H157Y TREM2相关的增强的sTREM2可以减少 一辆β。出乎意料的是，我们还观察到，与sTREM2不同，H157Y TREM2抑制了小胶质细胞的激活 签名(修订中的手稿)，表明除了潜在的sTREM2依赖效应 与增强的sTREM2脱落相关，H157Y TREM2也可能与潜在的-TREM2丢失有关 与TREM2裂解和失活相关的功能表型。 一个关键问题仍然是H157Y TREM2如何增强Aβ清除，并与升高的 广告风险。我们的结果表明，TREM2缺失可以通过以下途径加重tau的分散和发病 提高小胶质细胞外切体中种子活性tau的分布(朱等人，2022)。我们的初步结果 也表明sTREM2增强了tau寡聚体在小胶质细胞中的内在化，并促进了 将tau内化为外体前间隔，这表明尽管H157Y TREM2赋予 与Aβ清除相关的神经保护作用，H157Y TREM2可能会加重tau病理 通过功能获得(STREM2)和功能丧失(TREM2裂解/失活)的综合效应。至 相对于Aβ和tau，我们提出了与H157Y TREM2相关的解密增益和功能损失效应 使用小鼠AD(5xFAD，PS19；AAV-tau弥散模型)和人类细胞模型(ESC-Tau)的组合 小胶质细胞模型)以区分TREM2KO、H157Y和sTREM2对Aβ和tau的影响 H157Y-TREM2对小鼠和人的病理和小胶质细胞激活状态及其区别作用 胚胎干细胞来源的小胶质细胞在hMCSF/5xFAD小鼠脑内的异种移植模型。这将使我们能够 破译AD病理中与H157Y TREM2相关的sTREM2依赖和独立效应。

PROJECT SUMMARY Alzheimer’s disease (AD) is the most prominent neurodegenerative disorder worldwide, and is pathologically characterized by Aβ plaques and tau tangles. Growing evidence indicates that microglial receptors such as TREM2 can play a role in both Aβ and tau pathology. TREM2 is proteolytically processed by ADAM proteases to generate soluble TREM2 (sTREM2). Although sTREM2 levels are significantly elevated in cerebrospinal fluid (CSF) along with tau and phospho-tau during early stages of AD onset, nothing was known with respect to sTREM2 function prior to our previous R01 study. Our group and others established that TREM2 is a potential Aβ receptor which mediates microglial activation in response to Aβ oligomers (Zhao et al., 2018). Moreover, our prior mPI team showed that AAV-mediated sTREM2 expression could reduce Aβ accumulation and promote microglial activation (Zhong et al., 2019). Interestingly, the TREM2 cleavage site was recently shown to occur at H157, where an AD-associated H157Y TREM2 variant enhanced TREM2 ADAM-dependent TREM2 cleavage. We therefore integrated the H157Y mutation into the murine Trem2 locus, and characterized effects of H157Y Trem2 in a 5xFAD background. We found that similar to sTREM2 expression, H157Y Trem2 reduced Aβ plaque load and enhanced Aβ clearance, suggesting that enhanced sTREM2 associated with H157Y Trem2 can reduce Aβ. Unexpectedly, we also observed that unlike sTREM2, H157Y Trem2 suppressed microglial activation signatures (manuscript in revision), suggesting that in addition to potential sTREM2-dependent effects associated with enhanced sTREM2 shedding, H157Y Trem2 may also be associated with potential loss-of- function phenotypes linked to elevated TREM2 cleavage and inactivation. A key question remains how H157Y Trem2 can enhance Aβ clearance, and is yet associated with elevated AD risk. Our results indicate that Trem2 deletion can aggravate tau dispersion and pathogenesis through enhancing distribution of seed-competent tau in microglial exosomes (Zhu et al., 2022). Our preliminary results also indicate that sTREM2 enhances internalization of tau oligomers in microglia, and promotes trafficking of internalized tau to pre-exosomal compartments, which suggests that although H157Y Trem2 confers neuroprotective effects with respect to Aβ clearance, H157Y Trem2 could potentially aggravate tau pathology through combined gain-of-function (sTREM2) and loss-of-function (TREM2 cleavage/inactivation) effects. To decipher gain and loss-of-function effects associated with H157Y Trem2 with respect to Aβ and tau, we propose to use a combination of mouse AD (5xFAD, PS19; AAV-tau dispersion models) and human cell models (ESC- derived microglia models) to distinguish between effects of Trem2 KO, H157Y and sTREM2 on Aβ and tau pathology and microglial activation states, as well as distinguish effects of H157Y TREM2 in mouse and human microglia using ESC-derived xenotransplantation models in hMCSF/5xFAD mouse brain. This will allow us to decipher sTREM2-dependent and independent effects associated with H157Y TREM2 in AD pathology.