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

通过增强 MET 受体酪氨酸激酶信号传导来拯救阿尔茨海默病小鼠模型中的突触病理学

• 批准号: 10507127
• 负责人: Shenfeng Qiu
• 金额: $ 42.21万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10507127
• 关键词: Address; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Amyloid; Amyloid beta-Protein; Biochemical; Brain; Breeding; Cells; Cerebrospinal Fluid; Data; Dementia; Dendritic Spines; Development; Excitatory Synapse; Exhibits; Functional disorder; Genetic; Glutamates; Goals; HGF gene; Hippocampus (Brain); Human; Immune; Impaired cognition; Impairment; Knock-in; Knock-in Mouse; Laboratories; Lasers; Lead; Learning; Ligands; Literature; Long-Term Potentiation; Maps; Mediating; Memory; Memory Loss; Molecular; Molecular Target; Morphogenesis; Morphology; Mus; Natural regeneration; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peripheral; Physiology; Prosencephalon; Proteins; Public Health; Receptor Protein-Tyrosine Kinases; Research; Scanning; Senile Plaques; Signal Transduction; Signaling Protein; Slice; Societies; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Therapeutic Intervention; Tissues; Transgenic Organisms; Treatment Efficacy; Vertebral column; Work; abeta deposition; brain cell; cell type; density; excitatory neuron; functional loss; morris water maze; mouse model; neuromechanism; neuroprotection; novel; patch clamp; programs; socioeconomics; synaptic function; synaptogenesis; tau Proteins; tau-1; transcriptome; transcriptome sequencing

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.

项目摘要/摘要 阿尔茨海默氏病（AD）对我们的社会施加了压倒性的社会经济负担 AD脑的标志是在您的神经著作，TAU和Aβ的退化皮质神经元 细胞和功能水平，以突触功能受损和突触丧失的特征 前脑区域，表现为被破坏的突触塑料，学习，记忆和一般智力。 概括AD病理某些方面的小鼠模型已广泛地用于研究 神经变性的机制和治疗干预治疗的评估。 揭示了在早期在兴奋性神经元中大量表达的Met受体酪氨酸激酶 在成年大脑中，发育阶段的功能与成年大脑中的突触信号蛋白一样，在AD大脑中降低。 MET的激活启动了脱位信号传导，该信号传导在神经营养和神经保护作用 但是，多个神经退行性小鼠模型。 已经调查了该提案的目标是测试AD Mousel中的突触 通过增强的MET介导的信号恢复。 发育中的皮质回路中的信号传导促进了树突状的脊柱形成和突触形成。 电路连通性，并控制兴奋性突触成熟的时间。 使用在PI实验室中创建的独特的“人源化” HMET条件敲击（CKI）小鼠的数据显示 转录组轮廓改变，增加海马长期增强（LTP）和学习和学习 记忆此外，成人海马CA1神经元中的高架 传播和脊柱密度增加，指示从头突触发生。 导致了以下假设：在神经变性之前增强了MET介导的多效性信号传导一个人，一个人，一个人，一个人 淀粉样蛋白AD小鼠模型（5xFAD）可能会挽救破坏的分子途径，减少病理 突触损失，并提出认知能力下降。 支撑以测试HMET-CKI信号是否减轻了分子和病理变化（AIM 1）和 减轻5xFAD小鼠模型中的突触损失和认知下降（AIM 2） 假设的有益作用突出显示了内源性多效性的潜力 发育分子信号传导是AD中神经营养疗法的新候选者。