Astrocyte-secreted proteins as modulators of neurodegeneration in Down Syndrome and Alzheimers Disease

星形胶质细胞分泌的蛋白质作为唐氏综合症和阿尔茨海默病神经变性的调节剂

基本信息

批准号：
10644858
负责人：
Ashley N Brandebura
金额：
$ 12.42万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
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：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644858
关键词：
Acceleration Address Adult Affect Age Age of Onset Aging Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Astrocytes Autopsy Behavioral Biological Biology Biotin Brain California Cells Characteristics Chromosome 21 Clinical Compensation Congenital chromosomal disease Data Data Set Databases Dementia Dendrites Dendritic Spines Deposition Disease Disease Progression Down Syndrome Endoplasmic Reticulum Event Foundations Future Gene Dosage Gene Proteins Genetic Genetic Transcription Growth Hippocampus Human Impaired cognition In Vitro Individual Intellectual functioning disability Investigation Knockout Mice Label Laboratories Length Link Literature Live Birth Location Mass Spectrum Analysis Mediating Memory impairment Mentors Messenger RNA Mining Molecular Mus Mutation Neonatal Nerve Degeneration Neurodevelopmental Disorder Neurologist Pathogenesis Pathologic Pathology Patients Peptide Fragments Phenocopy Phenotype Population Protein Databases Protein Secretion Proteins Proteomics Public Health Reporting Research Research Personnel Role Senile Plaques Series Stains Streptavidin Synapses Synapsins System Technology Testing Tissues Training Transcript Trisomy Universities Vertebral column Viral Virus Work abeta accumulation astrogliosis career cell type comparison control conditioned fear density differential expression experimental study hippocampal pyramidal neuron in vivo interest knock-down lifetime risk mRNA Expression mouse Ts65Dn mouse model neuropathology novel overexpression pleiotrophin single nucleus RNA-sequencing spatial memory therapeutic target

项目摘要

Project Summary/Abstract Down Syndrome (DS) is a neurodevelopmental disorder caused by trisomy of chromosome 21, and with age a majority of DS patients develop neuropathological hallmarks associated with Alzheimer’s Disease (AD), including amyloid plaque deposition and astrogliosis, as well as clinical dementia (cooccurrence of DS with AD is DS-AD). Amyloid precursor protein (APP) mutations are linked to AD, and DS patients have triplication of the APP gene, suggesting this as a contributing factor to the overlapping pathology. Research suggests astrocytes are regulators of both DS and AD disease progression. Astrocytes modulate synapses through the release of secreted proteins, and recent work suggests that astrocyte protein secretion is dysregulated in both DS and AD. The Allen lab identified >700 astrocyte-secreted proteins dysregulated in the Ts65Dn mouse model of DS at neonatal timepoints. Of interest, secretion of the pro-growth protein pleiotrophin (Ptn) was >4x down-regulated from Ts65Dn astrocytes, and subsequent investigations of Ptn knockout mice revealed that they phenocopy Ts65Dn mice in many aspects, including decreased dendrite length and spine density. Single nucleus RNA- Sequencing studies show that subsets of “disease-associated” astrocytes in AD down-regulate transcripts encoding for many pro-synaptogenic factors, including Ptn. The main hypotheses of this proposal are that: 1) a network of overlapping astrocyte-secreted proteins is altered in DS-AD and AD, and 2) decreased Ptn secretion from astrocytes contributes to disease progression in DS-AD and AD. This proposal takes an unbiased approach to characterize changes in the astrocyte secretome in DS-AD and AD mouse models, as well as a targeted approach to investigate the potential for Ptn to rescue neuropathological phenotypes. Aim 1/K99 utilizes biotin- mediated proximity labeling (an endoplasmic reticulum localized TurboID virus) to create novel datasets for the in vivo astrocyte-specific secretome in DS-AD and AD mouse models at early, middle and late stages of disease. This aim provides the investigator with extensive training in mass spectrometry technology and quantitative proteomics analysis. Aim 2/R00 employs viral-mediated Ptn overexpression in astrocytes to investigate if Ptn can rescue spine density, astrogliosis and spatial memory impairments in DS-AD and AD mouse models. Additionally, the investigator will utilize the astrocyte-specific secretome datasets from Aim 1 to investigate other protein candidates in their future laboratory. The mentoring team consists of Dr. Nicola Allen, a leader in astrocyte biology; Dr. Alan Saghatelian, who will provide expertise in quantitative proteomics; Dr. Jolene Diedrich, mass spectrometry core director; Dr. Nick Andrews, behavioral core director; and Dr. Douglas Galasko, a neurologist specializing in dementia and Associate Director of the Alzheimer’s Disease Research Center (ADRC) at the University of California San Diego (UCSD). The work will take place at the world class Salk Institute for Biological Studies and establish networking connections at the ADRC and UCSD, providing an essential foundation for Dr. Brandebura’s independent research career focused on astrocyte-secreted proteins in neurodegeneration.

项目摘要/摘要唐氏综合症（DS）是由21染色体三体造成的神经发育障碍，随着年龄的增长大多数DS患者发展与阿尔茨海默氏病（AD）相关的神经病理学标志，包括淀粉样菌斑沉积和星形胶质症以及临床痴呆（与AD的DS共发生为DS-AD）。淀粉样蛋白前体蛋白（APP）突变与AD相关，DS患者的APP基因三重这表明这是导致重叠病理的一个因素。研究表明星形胶质细胞是 DS和AD疾病进展的调节剂。星形胶质细胞通过释放调节突触分泌的蛋白质和最近的工作表明，在DS和AD中，星形胶质细胞蛋白分泌均失调。艾伦实验室（Allen Lab 新生儿时间点。感兴趣的是，促增长蛋白多叶酸蛋白（PTN）的分泌> 4倍。从TS65DN的星形胶质细胞以及随后对PTN敲除小鼠的研究表明它们是表观的 TS65DN小鼠在许多方面，包括树突长度和脊柱密度降低。单核RNA- 测序研究表明，AD下调的转录本中的“相关”星形胶质细胞的子集编码包括PTN在内的许多促突出因素。该提议的主要假设是：1） DS-AD和AD中改变了重叠星形胶质细胞分泌蛋白的网络，以及2）改进的PTN分泌来自星形胶质细胞有助于DS-AD和AD的疾病进展。该建议采用公正的方法为了表征DS-AD和AD鼠标模型中星形胶质细胞分泌组的变化，以及目标研究PTN营救神经病理表型的潜力的方法。 AIM 1/K99使用生物素 - 介导的接近标记（内质网局部涡轮病毒）为创建新的数据集 DS-AD和AD小鼠模型的体内星形胶质细胞特异性分泌组在疾病的早期，中和晚期。这个目的为研究人员提供了质谱技术和定量方面的广泛培训蛋白质组学分析。 AIM 2/R00员工在星形胶质细胞中病毒介导的PTN过表达，以调查PTN是否存在可以挽救DS-AD和AD小鼠模型中的脊柱密度，星形胶质细胞增多和空间记忆障碍。此外，研究者将利用AIM 1的星形胶质细胞特定的秘密数据集来调查其他蛋白质候选者未来实验室。指导团队由星形胶质细胞领导者Nicola Allen博士组成生物学; Alan Saghatelian博士将提供定量蛋白质组学方面的专业知识；乔琳·迪德里奇博士，马萨诸塞州光谱核心主管；行为核心主任尼克·安德鲁斯（Nick Andrews）博士；神经病学家道格拉斯·加拉斯科（Douglas Galasko）博士专门研究痴呆症和阿尔茨海默氏病研究中心（ADRC）的副主任加州大学圣地亚哥分校（UCSD）。这项工作将在世界一流的生物学研究所举行在ADRC和UCSD上进行研究并建立网络连接，为Dr. Brandebura的独立研究生涯的重点是神经变性的星形胶质细胞分泌蛋白。