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.

项目概要/摘要唐氏综合症（DS）是一种由21号染色体三体引起的神经发育障碍，随着年龄的增长大多数 DS 患者会出现与阿尔茨海默病 (AD) 相关的神经病理学特征，包括淀粉样斑块沉积和星形胶质细胞增生，以及临床痴呆（DS 与 AD 共存为 DS-AD）。淀粉样前体蛋白 (APP) 突变与 AD 相关，DS 患者存在 APP 基因的三倍体，研究表明星形胶质细胞是导致重叠病理学的一个因素。 DS 和 AD 疾病进展的调节因子通过释放分泌蛋白，最近的研究表明星形胶质细胞蛋白分泌在 DS 和 AD 中均失调。 Allen 实验室在 DS 的 Ts65Dn 小鼠模型中发现了超过 700 种星形胶质细胞分泌蛋白失调。有趣的是，促生长蛋白多效蛋白 (Ptn) 的分泌下调了 4 倍以上。来自 Ts65Dn 星形胶质细胞，随后对 Ptn 敲除小鼠的研究表明，它们的表型 Ts65Dn 小鼠在许多方面都有所改善，包括树突长度和单核 RNA 密度降低。测序研究表明 AD 中“与疾病相关”的星形胶质细胞亚群下调转录本编码许多促突触因子，包括 Ptn。该提案的主要假设是：1） DS-AD 和 AD 中重叠的星形胶质细胞分泌蛋白网络发生改变，2) Ptn 分泌减少星形胶质细胞导致 DS-AD 和 AD 的疾病进展该提案采用公正的方法。表征 DS-AD 和 AD 小鼠模型中星形胶质细胞分泌组的变化，以及靶向研究 Ptn 拯救神经病理表型的潜力的方法 Aim 1/K99 利用生物素- 介导的邻近标记（一种内质网定位的 TurboID 病毒）来创建新的数据集 DS-AD 和 AD 小鼠模型在疾病早期、中期和晚期的体内星形胶质细胞特异性分泌组。这一目标为研究人员提供了质谱技术和定量方面的广泛培训。 Aim 2/R00 利用星形胶质细胞中病毒介导的 Ptn 过度表达来研究 Ptn 是否存在。可以挽救 DS-AD 和 AD 小鼠模型中的脊柱密度、星形胶质细胞增生和空间记忆障碍。此外，研究人员将利用目标 1 中的星形胶质细胞特异性分泌组数据集来研究其他指导团队由星形胶质细胞领域的领导者 Nicola Allen 博士组成。生物学；Alan Saghatelian 博士，他将提供定量蛋白质组学方面的专业知识；Jolene Diedrich 博士，马萨诸塞州光谱测定核心主任；尼克·安德鲁斯博士，行为核心主任；道格拉斯·加拉斯科博士，神经学家；专攻痴呆症，现任阿尔茨海默病研究中心 (ADRC) 副主任这项工作将在世界一流的索尔克生物研究所进行。在 ADRC 和 UCSD 学习并建立网络联系，为 Dr. 布兰德布拉的独立研究生涯主要集中在神经退行性疾病中星形胶质细胞分泌的蛋白质。