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.

概括 最近的证据表明，免疫和神经网络功能障碍形成了一种恶性循环，可驱动 阿尔茨海默氏病的发病机理（AD）。在髓样细胞2（Trem2）和 它的结合伴侣，Tyro蛋白酪氨酸激酶结合蛋白（Tyrobp）均由 小胶质细胞，大脑的居民免疫细胞。损害TREM2或Tyrobp功能的遗传变异 增加发展AD或其他类型的痴呆症的风险。几项研究表明，这样 变体还会影响AD病理的发展，例如淀粉样蛋白斑块和神经原纤维缠结，但 一些结果表明对病理与功能的影响之间存在困惑的差异 改变。由于这个和其他原因，重要的是研究其他机制，尤其是过程 有可能导致与广告相关的认知下降。去年，我们报道了减少 Trem2的功能加剧了小鼠化学诱导的癫痫。从那以后，我们发现了类似的 暴君表达降低的小鼠异常。此外，我们发现表达的敲蛋白小鼠 当受到挑战时 引起癫痫的药物或越过会发展出突出淀粉样蛋白的应用敲击小鼠菌株 病理。这些发现增加了小胶质细胞需要Trem2和Tyrobp抑制网络的可能性 过度兴奋。该假设的潜在临床意义通过证明 在很大一部分的AD患者中，非敏感的癫痫样活动，认知能力下降的速度更快 与没有可检测到的癫痫病活性的零星AD患者相比。而大多数研究 TREM2和Tyrobp专注于与痴呆症的遗传联系或这些基因产物的影响 相关病理，我们的建议将检验小胶质细胞需要表达正常水平的新假设 TREM2和Tyrobp有效地感知和抑制网络过度兴奋性，这可能有助于 AD和相关痴呆症的认知能力下降。为了检验这一总体假设，我们将确定（1）是否 霸凌和兴奋性和广告相关的小鼠的网络过度刺激性的性能不佳 模型，（2）TREM2的过表达可降低化学诱导的网络过度兴奋性以及是否是否 这种效果需要泰洛布，（3）TREM2或Tyrobp的功能障碍如何损害 小胶质细胞抑制细胞培养模型中异常神经元活性。提出的实验的结果 将阐明这些分子和小胶质细胞在AD发病机理中的作用。他们也可以提供 在开发AD和相关疾病的免疫调节治疗方面的有用指导。