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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

项目概要阿尔茨海默病（AD）是一种影响全球数百万人的神经退行性疾病。 AD 包括病理性神经元细胞死亡、突触功能障碍和相应的行为缺陷。然而，AD 病理学的分子基础仍不清楚。磷酸二酯酶 2 (GDE2) 是六跨膜蛋白家族的成员，可释放来自细胞表面的糖基磷脂酰肌醇 (GPI) 锚定蛋白在神经系统的发育过程中， GDE2 利用其 GPI 锚定裂解促进中枢神经系统 (CNS) 中的神经元分化在衰老过程中，GDE2 的缺失会导致 AD 样表型，包括 Aβ 产生、突触等。在人类 AD 脑组织中，GDE2 在细胞内异常积累。与健康对照大脑相比，表明 GDE2 功能障碍可能导致 AD 病理生理学。 GDE2 通过调节表面介导其调节 Aβ 产生和突触蛋白损失的功能 GPI 锚定蛋白 RECK（具有 Kazal 基序的富含半胱氨酸的回复诱导蛋白）的表达。 RECK 是一种有效的金属蛋白酶抑制剂，最近与经典 Wnt 信号传导有关。膜 RECK 的表达导致突触蛋白的减少，与 Aβ 的产生无关 AD 患者大脑中膜 RECK 的水平高度升高，这是该提议的指导假设。 GDE2 通过 RECK 的裂解来调节突触功能，并且该通路的功能障碍有助于 AD 突触病理学和认知变化。我将通过多管齐下的方式来检验这一假设。在目标 1 中，我将评估将利用电生理学、行为学和分子方法的方法。小鼠突触前和突触后功能对 GDE2 的要求在目标 2 中，我将执行各种行为。实验测试认知以确定缺乏 GDE2 的小鼠的相应行为异常。目标 3，我将探讨 GDE2 和 RECK 影响突触生物学的分子机制。这些实验将扩展我们对 GDE2 在突触生物学中所扮演的角色的了解，并有可能帮助我们更好地了解 AD 病理学的机制基础。这项研究将以高度的方式进行。协作环境，我将有很多机会接受优质的指导和培训，发展我的写作和演讲技巧，并成长为更多初级科学家的导师和老师。总的来说，Kirschstein-NRSA 的资助将支持我旨在发现突触生物学的研究潜在的神经退行性疾病和我作为一名独立科学家的发展。