Investigating pathways of hippocampal synaptic funtion: potential implications for Alzheimer's disease

研究海马突触功能的途径：对阿尔茨海默病的潜在影响

• 批准号: 10678164
• 负责人: Daniel Daudelin
• 金额: $ 4.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678164
• 关键词: Abeta synthesis; Address; Adult; Affect; Age; Age Months; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anxiety; Behavior; Behavioral; Binding; Biochemical; Biology; Brain; Cell Surface Proteins; Cells; Central Nervous System; Cognition; Cognitive; Collaborations; Confocal Microscopy; Defect; Dementia; Dendritic Spines; Deposition; Development; Disease; Electrophysiology (science); Exhibits; Frequencies; Functional disorder; GPI Membrane Anchors; Glycosylphosphatidylinositols; Grant; Hippocampus; Human; Impaired cognition; Integral Membrane Protein; Knowledge; Language; Ligands; Long-Term Depression; Long-Term Potentiation; Longitudinal Studies; Measures; Mediating; Membrane; Memory; Mentors; Mentorship; Metalloproteases; Molecular; Molecular Probes; Motor Activity; Mus; National Research Service Awards; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Differentiation; Neurons; Outcome; Pathology; Pathway interactions; Patients; Persons; Phenotype; Physiologic pulse; Play; Property; Protein Family; Proteins; Regulation; Research; Role; Scientist; Series; Short-Term Memory; Structure; Surface; Synapses; Synaptic plasticity; Techniques; Testing; Therapeutic Intervention; Training; Visualization; WNT Signaling Pathway; Walking; Work; Writing; aged; beta secretase; biocytin; brain tissue; cognitive change; cognitive skill; collaborative environment; comparison control; cysteine rich protein; design; experimental study; extracellular; gain of function; gamma secretase; glycerophosphodiester phosphodiesterase; hippocampal pyramidal neuron; inhibitor; insight; lentivirally transduced; member; mind control; mouse model; neuron loss; neurotoxic; new therapeutic target; novel; patch clamp; postsynaptic; preservation; presynaptic; receptor; skills; synaptic function; targeted treatment; tau Proteins; teacher

Project Summary Alzheimer's Disease (AD) is a neurodegenerative disease affecting millions of people around the globe. AD pathology includes neuronal cell death, synaptic dysfunction, and corresponding behavioral deficits. However, the molecular basis underlying AD pathologies remains unclear. Glycerophosphodiester phosphodiesterase 2 (GDE2) is a member of a six-transmembrane protein family that releases glycosylphosphatidylinositol (GPI)-anchored proteins from the cell surface. In the developing nervous system, GDE2 promotes neuronal differentiation in the central nervous system (CNS) using its GPI-anchor cleavage mechanism. During aging the loss of GDE2 leads to AD-like phenotypes, including Aβ production, synaptic protein loss, and neurodegeneration. In human AD brain tissue, GDE2 aberrantly accumulates intracellularly compared to healthy control brains, suggesting that GDE2 dysfunction could contribute to AD pathophysiology. GDE2 mediates its functions in regulating Aβ production and synaptic protein loss via regulation of surface expression of the GPI-anchored protein RECK (reversion-inducing cysteine-rich protein with Kazal motifs). RECK is a potent inhibitor of metalloproteases and is recently implicated in canonical Wnt signaling. Increased expression of membrane RECK leads to a decrease in synaptic proteins that is independent of Aβ production and levels of membrane RECK are highly elevated in AD patient brain. The guiding hypothesis of this proposal is that GDE2 regulates synaptic function through the cleavage of RECK and that dysfunction of this pathway contributes to AD synaptic pathology and cognitive changes. I will test this hypothesis through a multi-pronged approach that will utilize electrophysiological, behavioral, and molecular approaches. In Aim 1, I will assess the requirement for GDE2 in pre- and post-synaptic function in mice. In Aim 2, I will perform a variety of behavioral experiments testing cognition to define corresponding behavioral abnormalities in mice lacking GDE2. Finally, in Aim 3, I will probe the molecular mechanism through which GDE2 and RECK act to affect synaptic biology. These experiments will expand our knowledge of the role GDE2 plays in synaptic biology and could potentially help us better understand the mechanistic basis of AD pathologies. This research will be performed in a highly collaborative environment, where I will have numerous opportunities to receive quality mentorship and training, to develop my written and presentation skills, and to grow as a mentor and teacher to more junior scientists. Overall, the Kirschstein-NRSA grant will support both my research aimed at discovering the synaptic biology underlying neurodegeneration and my development as an independent scientist.

项目摘要 阿尔茨海默病(AD)是一种影响全球数百万人的神经退行性疾病。 AD病理包括神经细胞死亡、突触功能障碍和相应的行为缺陷。 然而，阿尔茨海默病发病的分子基础仍不清楚。甘油磷酸二酯 磷酸二酯酶2(GDE2)是六跨膜蛋白家族中的一员，可释放 糖基磷脂酰肌醇(GPI)--细胞表面的锚定蛋白。在发育中的神经系统中， GDE2通过其GPI锚点切割促进中枢神经系统(CNS)神经元分化 机制。在衰老过程中，GDE2的丢失会导致类似AD的表型，包括Aβ的产生，突触 蛋白质丢失和神经退化。在阿尔茨海默病患者脑组织中，GDE2在细胞内异常蓄积 与健康对照组相比，GDE2功能障碍可能与AD的病理生理学有关。 Gde2通过表面调节调节Aβ合成和突触蛋白丢失的功能 GPI锚定蛋白RECK(具有Kazal基序的逆转诱导富含半胱氨酸蛋白)的表达 RECK是一种有效的金属蛋白水解酶抑制剂，最近被发现与典型的Wnt信号有关。增加了 膜RECK的表达导致突触蛋白减少，这种减少不依赖于Aβ的产生 阿尔茨海默病患者脑组织中RECK膜蛋白水平显著升高。这一提议的指导假设 GDE2通过RECK的裂解和该通路的功能障碍来调节突触功能 有助于AD突触病理和认知改变。我将通过多管齐下的方式检验这一假设。 将利用电生理、行为和分子方法的方法。在目标1中，我将评估 小鼠突触前、后功能对GDE2的需求。在目标2中，我将表演各种行为 测试认知能力的实验，以确定缺乏GDE2的小鼠的相应行为异常。最后，在 目的3，探讨GDE2和RECK影响突触生物学的分子机制。 这些实验将扩大我们对GDE2在突触生物学中所起作用的了解，并有可能 帮助我们更好地理解AD病理的机制基础。这项研究将在一个高度 协作环境，在那里我将有很多机会接受高质量的指导和培训， 发展我的写作和演讲技能，并成长为更多初级科学家的导师和老师。 总体而言，Kirschstein-NRSA拨款将支持我旨在发现突触生物学的两项研究 潜在的神经退化和我作为一名独立科学家的发展。