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，使脑细胞与提供依赖经验的可塑性的基板来推动自适应行为。改变力量特定细胞或神经元之间的突触被认为是较高的大脑功能的基础学习和记忆，而在许多神经病理性中观察到突触降解，例如阿尔茨海默氏病（AD）和相关痴呆症。尽管突触交流具有明显的意义，但突触功能受损，AD症状的进展和认知能力下降之间的关系仍然存在不清楚。然而，最近的分子显微镜突破可以直接成像阿尔茨海默氏病小鼠模型中的病理突触缺陷。我们的方法是荧光标记突触蛋白和AD标记物在疾病进展过程中使用体内两光子进行跟踪显微镜。通过成像包括整个皮质和海马电路的大量突触，我们努力详细了解分子病理如何影响突触生理，最终引起认知能力下降。这种方法将产生突触进展的详细时间过程认知阿尔茨海默氏症的病理可能会揭示有效的治疗窗口和新颖的治疗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