Rescue of synaptic pathology in an Alzheimer's mouse model by enhancing MET receptor tyrosine kinase signaling

项目摘要/摘要 阿尔茨海默病(AD)给我们的社会带来了巨大的社会经济负担。关键病理 阿尔茨海默病大脑的特征是皮质神经元变性，伴有神经原纤维缠结、Tau和Aβ。在 细胞和功能水平，阿尔茨海默病的特点是突触功能受损和突触丢失 前脑区域，表现为突触可塑性、学习、记忆和一般智力的紊乱。 重述AD病理某些方面的小鼠模型已被广泛应用于研究 神经退行性变的机制和评估治疗干预的效果。近现代文学 揭示MET受体酪氨酸激酶，早期在兴奋性神经元中大量表达 发育阶段在成人大脑中作为突触信号蛋白发挥作用，在AD大脑中减少。 MET的激活启动了一种多效性信号，发挥了神经营养和神经保护作用。 多种神经退行性变小鼠模型。然而，MET信号如何影响AD发病机制尚未见报道 被调查过了。这项提议的目标是测试AD小鼠模型中的突触病理是否可以 通过增强的MET介导的信号转导而获救。这个研究小组最近的研究表明，Meet 皮质环路发育中的信号促进树突棘的形成和突触的形成 电路连接，并控制兴奋性突触成熟的时间。更耐人寻味的是，初步 使用PI实验室创造的独特的人源化HMET条件性敲门(CKI)小鼠的数据显示 转录组谱改变，海马长时程增强(LTP)增加，学习和学习能力增强 记忆。此外，成年海马CA1区神经元中MET信号的升高导致突触增强 传输和增加的脊椎密度表明新的突触发生。这些令人兴奋的结果 导致了一种假说，即在神经变性之前增强MET介导的多效性信号转导 淀粉样阿尔茨海默病小鼠模型(5xFAD)可挽救受损的分子通路，减轻病理改变 突触缺失，缓解认知功能衰退。为了解决这一假设，有两个具体目标 建议测试HMET-CKI信号是否减轻分子和病理变化(目标1)和 减轻5xFAD小鼠模型中的突触丢失和认知功能下降(目标2)。影响： HMET信号的假设有益效应突出了内源性多效性的潜力 发育分子信号作为阿尔茨海默病神经营养治疗的新候选者。

Project Summary/Abstract Alzheimer's disease (AD) imposes an overwhelming socioeconomic burden on our society. Key pathological hallmarks of the AD brain are degenerating cortical neurons with neurofibrillary tangles, Tau, and Aβ. At the cellular and functional level, AD is characterized by impaired synaptic function and synapse loss across many forebrain regions, and is manifested as disrupted synaptic plasticity, learning, memory, and general intellect. Mouse models recapitulating certain aspects of AD pathology have been extensively employed to study mechanisms of neural degeneration and assess efficacy of therapeutic interventions. Recent literature revealed that MET receptor tyrosine kinase, heavily expressed in the excitatory neurons at early developmental stages yet functions as a synaptic signaling protein in the adult brain, is reduced in AD brain. Activation of MET initiates a pleiotropic signaling that exerts neurotrophic and neuroprotective effects in multiple neurodegenerative mouse models. However, how MET signaling affects AD pathogenesis has not been investigated. The goal of this proposal is to test whether synaptic pathology in an AD mouse model can be rescued by enhanced MET-mediated signaling. Recent work from this research team showed that MET signaling in the developing cortical circuits promotes dendritic spine formation and synaptogenesis, refines circuit connectivity, and controls the timing of excitatory synapse maturation. More intriguingly, preliminary data using unique ‘humanized’ hMET conditional knockin (cKI) mice created in the PI’s laboratory revealed altered transcriptome profiles, increased hippocampal long term potentiation (LTP) and enhanced learning and memory. In addition, elevated MET signaling in adult hippocampal CA1 neurons resulted in enhanced synaptic transmission and increased spine density indicative of de novo synaptogenesis. These exciting results have led to the hypothesis that enhancing MET-mediated pleiotropic signaling prior to neurodegeneration in an amyloid AD mouse model (5xFAD) may rescue the disrupted molecular pathways, reduce pathological synapse losses, and alleviate the cognitive decline. To address this hypothesis, two specific aims are proposed to test whether hMET-cKI signaling alleviates molecular and pathological changes (Aim 1) and mitigates the synaptic loss and cognitive decline (Aim 2) in the 5xFAD mouse model. Impact: The hypothesized beneficial effects of hMET signaling highlight the potential of an endogenous pleiotropic developmental molecular signaling as a novel candidate for neurotrophic therapy in AD.