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Longitudinal in vivo imaging of synaptic pathologies of Alzheimer's disease

阿尔茨海默病突触病理的纵向体内成像

基本信息

批准号：
9895142
负责人：
Austin Robert Graves
金额：
$ 45.03万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895142
关键词：
Adaptive Behaviors Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Amyloid Amyloid beta-Protein Amyloid deposition Animals Area Behavioral Biological Biological Markers Brain Brain region Cells Cessation of life Chronic Cognitive Cognitive deficits Communication Data Dementia Development Disease Disease Marker Disease Progression Disease model Dyes Excitatory Synapse Fluorescent Dyes Fright Functional disorder Genetic Glutamate Receptor Hippocampus (Brain)Human Image Impaired cognition Impairment Implant Knock-in Knock-in Mouse Label Lead Learning Ligands Memory Memory Loss Memory impairment Microscopy Modeling Molecular Molecular Profiling Monitor Mus Neocortex Nervous system structure Neurofibrillary Tangles Neurons Neurosciences Operative Surgical Procedures Optics PHluorin Pathogenesis Pathologic Pathology Physiology Population Proteins Rodent Model Signal Transduction Symptoms Synapses Techniques Therapeutic Intervention Time Visualization austin behavior test behavioral impairment behavioral phenotyping brain cell cognitive function conditioned fear cranium effective therapy experience human disease in vivo in vivo imaging innovation insight medical schools memory encoding memory recall molecular pathology mouse model neurological pathology novel novel strategies overexpression real time monitoring relating to nervous system serial imaging synaptic function tau Proteins tau aggregation tool two photon microscopy

项目摘要

The synapse is the fundamental unit of the nervous system, enabling communication between brain cells and providing a substrate for experience-dependent plasticity to drive adaptive behaviors. Altering the strength of synapses between specific cells or neuronal ensembles is thought to underlie higher brain functions such as learning and memory, whereas synaptic degradation is observed in many neurological pathologies, such as Alzheimer's disease (AD) and related dementias. Despite the clear significance of synaptic communication, the relationship between impaired synaptic function, progression of AD symptoms, and cognitive decline remains unclear. However, recent breakthroughs in molecular microscopy enable direct imaging of the progression of pathological synaptic deficits in mouse models of Alzheimer's disease. Our approach is to fluorescently tag synaptic proteins and AD markers to track them throughout disease progression using in vivo two-photon microscopy. By imaging large populations of synapses comprising entire cortical and hippocampal circuits, we strive to gain a detailed understanding of how molecular pathologies affect synaptic physiology and ultimately give rise to cognitive decline. This approach will yield a detailed time course of the progression of synaptic and cognitive Alzheimer's pathologies that may reveal effective treatment windows and novel avenues for therapeutic interventions for human disease.

突触是神经系统的基本单位，使脑细胞之间的沟通，为经验依赖的可塑性提供了一个基础，以驱动适应性行为。改变了特定细胞或神经元集合体之间的突触被认为是大脑高级功能的基础，然而，在许多神经病理学中观察到突触退化，例如阿尔茨海默病（AD）和相关痴呆。尽管突触通讯的重要性很明显，突触功能受损、AD症状进展和认知能力下降之间的关系仍然存在不清楚然而，最近分子显微镜的突破使直接成像的进展，阿尔茨海默病小鼠模型中的病理性突触缺陷。我们的方法是用荧光标记突触蛋白和AD标记物，以使用体内双光子在整个疾病进展中追踪它们显微镜通过对包括整个皮层和海马回路的大量突触进行成像，努力获得分子病理学如何影响突触生理学的详细了解，并最终导致认知能力下降这种方法将产生一个详细的时间过程的进展，突触和认知阿尔茨海默病的病理学，可能揭示有效的治疗窗口和新的途径，人类疾病的干预措施。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cross-modality supervised image restoration enables nanoscale tracking of synaptic plasticity in living mice.

DOI：
10.1038/s41592-023-01871-6
发表时间：
2023-06
期刊：
NATURE METHODS
影响因子：
48
作者：
Xu, Yu Kang T.;Graves, Austin R.;Coste, Gabrielle I.;Huganir, Richard L.;Bergles, Dwight E.;Charles, Adam S.;Sulam, Jeremias
通讯作者：
Sulam, Jeremias