Roles of TREM2 and TYROBP in AD-related Network Hyperexcitability

TREM2 和 TYROBP 在 AD 相关网络过度兴奋中的作用

• 批准号: 10718004
• 负责人: Lennart Mucke
• 金额: $ 283.31万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718004
• 关键词: Ablation; Adaptor Signaling Protein; Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Bicuculline; Binding; Binding Proteins; Biological Response Modifiers; Brain; Cell Culture Techniques; Cells; Chemicals; Dementia; Development; Disease; Epilepsy; Excitatory Neurotoxins; Genetic; Human; Immune; Immune System Diseases; Impaired cognition; Impairment; In Vitro; Knock-in; Knock-in Mouse; Link; Macrophage; Mediating; Microglia; Modeling; Mouse Strains; Mus; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathologic; Pathology; Pharmaceutical Preparations; Predisposition; Process; Protein Tyrosine Kinase; Reporting; Risk; Role; Runaway; Seizures; Senile Plaques; Signal Transduction; Slice; Synapses; TREM2 gene; TYRO Protein Tyrosine Kinase Binding Protein; Testing; Therapeutic; Variant; age related; amyloid pathology; brain cell; chemical reduction; clinically significant; epileptiform; excitotoxicity; experimental study; gene product; genetic variant; in vivo; kainate; mouse model; network dysfunction; neural network; novel; overexpression; protein function; risk variant

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.

总结 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， 阿尔茨海默病（AD）的发病机制。髓样细胞上表达的触发受体2（TREM2）和 其结合伴侣TYRO蛋白酪氨酸激酶结合蛋白（TYROBP）均由 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AD或其他类型痴呆症的风险。一些研究表明， 变异也影响AD病理学的发展，如淀粉样斑块和神经纤维缠结， 一些结果揭示了对病理和功能的影响之间令人困惑的差异， 改变。由于这一点和其他原因，重要的是要研究其他机制，特别是过程 有可能导致AD相关的认知能力下降。去年，我们报告说，减少 TREM2的功能加剧了小鼠中化学诱导的癫痫。从那时起，我们发现了类似的 TYROBP表达减少的小鼠中的异常。此外，我们发现， 人TREM2 R47 H AD风险变体在用以下刺激时也具有增加的网络过度兴奋性 一种致癫痫药物，或者当与一种App敲入小鼠品系杂交时， 病理这些发现提出了小胶质细胞需要TREM2和TYROBP来抑制网络的可能性。 兴奋过度这一假设的潜在临床意义是突出的研究表明， 在相当大比例的AD患者中存在非惊厥性癫痫样活动， 与没有癫痫样活动的散发性AD患者相比，虽然大多数研究 TREM2和TYROBP专注于与痴呆症的遗传联系或这些基因产物对痴呆症的影响。 相关的病理，我们的建议将测试新的假设，即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 AD和相关痴呆的认知能力下降。为了验证这个假设，我们将确定（1） TYROBP功能减退加重兴奋毒性和AD相关小鼠网络过度兴奋 模型，（2）TREM2的过表达降低了化学诱导的网络过度兴奋性， TYROBP是这种效应所必需的，以及（3）TREM2或TYROBP的功能减退如何损害TREM2或TYROBP的功能， 小胶质细胞抑制细胞培养模型中的异常神经元活动。拟议实验的结果 将阐明这些分子和小胶质细胞在AD发病机制中的作用。它们还可以提供 在AD和相关疾病的免疫调节治疗的发展中的有用的指导。