Targeting Endosomal dysfunction as a new source of biomarkers for Alzheimer's disease

将内体功能障碍作为阿尔茨海默病生物标志物的新来源

基本信息

批准号：
10367484
负责人：
Sabrina Alves Simoes Spassov
金额：
$ 50.8万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-15 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367484
关键词：
APLP1 gene Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloidosis Biological Biological Assay Biological Markers Brain Cell Adhesion Molecules Cells Cellular biology Cerebrospinal Fluid Cognitive Confocal Microscopy Consensus Core Protein Cytopathology Data Defect Development Diagnostic Disease Disease Progression Electron Microscopy Endosomes Enzyme-Linked Immunosorbent Assay Extracellular Space Frontotemporal Dementia Functional disorder Genes Genetic Goals Histopathology Human Image Knock-out Knockout Mice Lewy Body Disease Link Liquid Chromatography Measures Modeling Mus Mutant Strains Mice Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Parkinson Disease Participant Pathogenicity Pathology Pathway interactions Patients Peripheral Plasma Preparation Proteins Proteomics Sampling Senile Plaques Source Specificity Technology Testing Therapeutic Intervention Transgenic Mice Western Blotting amyloid pathology base beta secretase beta-site APP cleaving enzyme 1 biomarker discovery biomarker panel de novo mutation design drug discovery exosome genetic risk factor human pluripotent stem cell mouse model mutant nervous system disorder potential biomarker prodromal Alzheimer&apos s disease protein expression rare variant receptor specific biomarkers tandem mass spectrometry tau Proteins trafficking

项目摘要

Endosomal dysfunction is a well-accepted cell biological feature in Alzheimer’s disease (AD). However, biomarkers reflecting endosomal traffic defects are still lacking. Current imaging and cerebrospinal fluid (CSF) AD biomarkers focus primarily on the histopathology of the disease—that is, biomarkers that are linked to neurofibrillary tangles and amyloid plaques. This proposal is designed to expand this focus to develop biomarkers of the ‘cell biology’ of AD. Such biomarkers could potentially accelerate drug discovery, as therapeutic interventions are currently being developed that target endosomal trafficking defects in AD. Genetic and cell biology studies have previously linked the endosomal trafficking assembly Retromer to AD pathology. Most notable are deficiencies and rare mutations in retromer’s core protein, VPS35, and retromer’s receptor, SORL1. Depletion of either VPS35 or SORL1 mimics the core cytopathology in AD, enlarged endosomes in neurons, with concomitant mis-trafficking of endosomal cargoes. In an effort to characterize defects in the endocytic pathway resulting from retromer dysfunction, we recently completed a proteomic screen of CSF of VPS35 knock-out (KO) mice and control littermates. Among the proteins found elevated in the CSF of VPS35 KO mice were well established β-secretase BACE1 substrates, includingAPP (Amyloid Precursor Protein); APLP1/2 (Amyloid Beta Precursor Like Proteins 1 and 2); and CHL1 (Neuralcell adhesion molecule L1-like protein). Two of these proteins --APLP1 and CHL1-- were further validated inmouse CSF, and human CSF from cognitively healthy participants and prodromal AD patients. Collectively, our studies suggest BACE1 substrates as potential biomarkers of retromer-dependent endosomal dysfunction. However, since VPS35 is implicated in other neurodegenerative disorders, including Parkinson’s disease (PD), these new biomarkers may not be specific to AD. Therefore, relying on these exciting findings, but moving towards the development of a panel of biomarkers reflecting endosomal trafficking defects that are specific to AD, we will examine SORL1 mouse models and human pluripotent stem cell (hPSC) SORL1-derived neurons as a new source of biomarkers of endosomal trafficking. We will also investigate exosomes as an additional source of biomarkers of endosomal defects. Lastly, since Sorl1 protein levels are altered in AD and CSF from AD patients, we will examine SORL1 CSF levels as a potential biomarker for AD. Completion of this study will provide evidence that SORL1-dependent endosomal trafficking is a new source of biomarkers for AD. Moreover, we predict that the extensive studies here proposed will identify a unique and specific endosomal biomarker of the “cell biology” of AD.

内体功能障碍是阿尔茨海默病（AD）中公认的细胞生物学特征。目前仍缺乏反映内体交通缺陷的生物标志物。 AD 生物标志物主要关注该疾病的组织病理学，即与以下因素相关的生物标志物：该提案旨在扩大这一重点以开发神经原纤维缠结和淀粉样斑块。 AD“细胞生物学”的生物标记物可能会加速药物发现，例如目前正在开发针对 AD 内体运输缺陷的治疗干预措施。遗传和细胞生物学研究先前已将内体运输组装Retromer与 AD 病理学中最值得注意的是逆转录酶核心蛋白 VPS35 的缺陷和罕见突变。逆转录酶受体 SORL1 的 VPS35 或 SORL1 的耗尽模拟了 AD 的核心细胞病理学，放大了。神经元中的内体，伴随着内体货物的错误运输。为了描述由逆转录酶功能障碍引起的内吞途径缺陷的特征，我们最近完成了 VPS35 敲除 (KO) 小鼠和对照同窝小鼠脑脊液的蛋白质组筛选，发现 VPS35 KO 小鼠脑脊液中升高的蛋白质包括成熟的 β-分泌酶 BACE1 底物，包括 APP（淀粉样蛋白前体蛋白）；（淀粉样蛋白 β 前体样蛋白 1 和 2）；和 CHL1（神经细胞粘附分子 L1 样蛋白）。 APLP1 和 CHL1 蛋白在认知健康参与者和前驱 AD 患者的小鼠脑脊液和人类脑脊液中得到进一步验证，我们的研究表明 BACE1 底物是逆转录酶依赖性内体功能障碍的潜在生物标志物。然而，由于 VPS35 与其他神经退行性疾病有关，包括帕金森病 (PD)，这些新的生物标志物可能不是 AD 特有的，因此，依赖这些令人兴奋的发现，但令人感动。开发一组反映内体运输缺陷的生物标志物，这些缺陷是特定的 AD，我们将检查 SORL1 小鼠模型和人类多能干细胞 (hPSC) SORL1 衍生神经元作为内体运输生物标志物的新来源，我们还将研究外泌体作为额外的内容。最后，由于 AD 和 CSF 中的 Sorl1 蛋白水平发生了变化。 AD 患者，我们将检查 SORL1 CSF 水平作为 AD 的潜在生物标志物。提供证据表明 SORL1 依赖性内体运输是 AD 生物标志物的新来源。此外，我们预测这里提出的广泛研究将确定一个独特且具体的 AD“细胞生物学”的内体生物标志物。