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个恶性循环，导致 阿尔茨海默病 (AD) 的发病机制是骨髓细胞 2 (TREM2) 上表达的触发受体和 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，会损害 TREM2 或 TYROBP 的功能。 增加患阿尔茨海默氏症或其他类型痴呆症的风险。一些研究表明，这种情况。 变异也会影响 AD 病理的发展，例如淀粉样蛋白斑和神经原纤维缠结，但是 一些结果揭示了病理效应与功能效应之间令人困惑的差异 由于这个原因和其他原因，研究其他机制，特别是过程非常重要。 去年，我们报告说，减少AD相关的认知能力下降。 TREM2 的功能使小鼠化学诱发的癫痫恶化 从那时起，我们发现了类似的情况。 TYROBP 表达减少的小鼠中出现异常。此外，我们发现敲入小鼠表达。 人类 TREM2 R47H 的 AD 风险变体在受到以下挑战时也会增加网络过度兴奋性： 引起癫痫的药物或与产生显着淀粉样蛋白的 App 敲入小鼠品系杂交时 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。 研究表明，过度兴奋性具有潜在的临床意义。 相当大比例的 AD 患者出现非惊厥性癫痫样活动，并且认知能力下降更快 与那些没有癫痫样活动的散发性 AD 患者相比，大多数研究都发现了这种情况。 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 相关的病理学，我们的建议将测试小胶质细胞需要表达正常水平的新假设 TREM2 和 TYROBP 有效感知和抑制网络过度兴奋，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，我们将确定是否 (1) TYROBP 功能低下会加重兴奋性毒性和 AD 相关小鼠的网络过度兴奋性 模型，(2) TREM2 的过度表达会降低化学诱导的网络过度兴奋性，以及是否 TYROBP 是该效应所必需的，以及 (3) TREM2 或 TYROBP 功能减退如何损害 TREM2 或 TYROBP 的能力 小胶质细胞抑制细胞培养模型中的异常神经活动。 将阐明这些分子和小胶质细胞在 AD 发病机制中的作用。 为 AD 及相关疾病的免疫调节治疗的开发提供有用的指导。