Roles of TREM2 and TYROBP in AD-related Network Hyperexcitability

摘要 最近的证据表明，免疫和神经网络功能障碍形成了一个恶性循环，推动了 阿尔茨海默病(AD)的发病机制。髓系细胞上表达的触发受体2(TREM2)和 它的结合伙伴，酪氨酸激酶结合蛋白(TYROBP)，都是由 小胶质细胞，大脑的常驻免疫细胞。损害TREM2或TYROBP功能的遗传变异 增加患上阿尔茨海默病或其他类型痴呆的风险。几项研究已经证明，这种 变异也影响AD病理的发展，如淀粉样斑块和神经原纤维缠结，但 一些结果揭示了病理和功能上的影响之间令人困惑的差异。 改装。由于这个原因和其他原因，重要的是要研究其他机制，特别是进程 有可能导致与AD相关的认知能力下降。去年，我们报告说，减少 TREM2的功能加重化学诱导的小鼠癫痫。从那时起，我们发现了类似的 TYROBP表达降低的小鼠的异常。此外，我们发现敲门小鼠表达 人类TREM2 R47H的AD风险变异也增加了网络的超兴奋性 一种导致癫痫的药物，或者当与App敲击小鼠品系杂交时，会出现显著的淀粉样蛋白 病理学。这些发现增加了小胶质细胞需要TREM2和TYROBP来抑制网络的可能性 过度兴奋。研究表明，这一假说的潜在临床意义被突显出来。 相当大比例的AD患者的非惊厥性癫痫样活动和较快的认知功能下降 可检测到癫痫样活动的散发性AD患者与未检测到癫痫样活动的患者相比。虽然大多数研究都是 TREM2和TYROBP专注于痴呆症的遗传联系或这些基因产物对 相关病理学，我们的建议将检验小胶质细胞需要表达正常水平的 TREM2和TYROBP有效地感知和抑制网络过度兴奋，这可能有助于 阿尔茨海默病及相关痴呆患者的认知功能下降。为了检验这一总体假设，我们将确定(1) TYROBP功能低下加重兴奋性毒性和AD相关小鼠的网络过度兴奋性 模型，(2)TREM2的过度表达降低了化学诱导的网络过度兴奋性，以及 这种作用需要TYROBP，以及(3)TREM2或TYROBP功能低下如何损害 在细胞培养模型中抑制异常神经元活动的小胶质细胞。建议的实验结果 将阐明这些分子和小胶质细胞在AD发病机制中的作用。他们还可以提供 对AD和相关疾病的免疫调节治疗的发展提供了有用的指导。

SUMMARY Recent evidence suggests that immune and neural network dysfunctions form a vicious cycle that drives the pathogenesis of Alzheimer’s disease (AD). The triggering receptor expressed on myeloid cells 2 (TREM2) and its binding partner, the TYRO protein tyrosine kinase-binding protein (TYROBP), are both expressed by microglia, the resident immune cells of the brain. Genetic variants that impair the functions of TREM2 or TYROBP increase the risk of developing AD or other types of dementias. Several studies have demonstrated that such variants also affect the development of AD pathologies such as amyloid plaques and neurofibrillary tangles, but some of the results revealed perplexing discrepancies between effects on pathological versus functional alterations. For this and other reasons, it is important to investigate additional mechanisms, especially processes that have the potential to contribute to AD-related cognitive decline. Last year, we reported that reducing the function of TREM2 exacerbates chemically induced epilepsy in mice. Since then, we discovered similar abnormalities in mice with reduced expression of TYROBP. In addition, we found that knockin mice expressing the AD risk variant of human TREM2 R47H also have increased network hyperexcitability when challenged with an epilepsy-causing drug or when crossed onto an App knockin mouse strain that develops prominent amyloid pathology. These findings raise the possibility that microglia require TREM2 and TYROBP to suppress network hyperexcitability. The potential clinical significance of this hypothesis is highlighted by studies demonstrating nonconvulsive epileptiform activity in a substantial proportion of AD patients and a faster cognitive decline in sporadic AD patients with detectable epileptiform activity as compared to those without. While most studies of TREM2 and TYROBP have focused on genetic links to dementias or the effects of these gene products on related pathologies, our proposal will test the novel hypothesis that microglia need to express normal levels of TREM2 and TYROBP to effectively sense and suppress network hyperexcitability, which may contribute to cognitive decline in AD and related dementias. To test this overall hypothesis, we will determine whether (1) hypofunction of TYROBP exacerbates network hyperexcitability in excitotoxicity- and AD-related mouse models, (2) overexpression of TREM2 reduces chemically induced network hyperexcitability and whether TYROBP is required for this effect, and (3) how hypofunction of TREM2 or TYROBP impairs the ability of microglia to suppress aberrant neuronal activities in cell culture models. The results of the proposed experiments will shed light on the roles of these molecules and of microglia in the pathogenesis of AD. They could also provide useful guidance in the development of immune modulatory treatment for AD and related disorders.