Endosomal dysfunction, a new source of biomarkers for Alzheimer's disease.

内体功能障碍，阿尔茨海默病生物标志物的新来源。

基本信息

批准号：
10471930
负责人：
Sabrina Alves Simoes Spassov
金额：
$ 20.25万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471930
关键词：
APLP1 gene APLP2 gene Address Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid beta-Protein Amyloid beta-Protein Precursor Biological Biological Assay Biological Markers Brain Cell Culture Techniques Cellular biology Cerebrospinal Fluid Cognitive Consensus Core Protein Culture Media Cytopathology Data Defect Development Diagnostic Disease Electron Microscopy Endosomes Frontotemporal Dementia Functional disorder Genetic Goals Histopathology Human Image Knockout Mice Link Measures Mus Mutation Neural Cell Adhesion Molecule L1 Neurofibrillary Tangles Neurons Outcome Parkinson Disease Participant Pathogenicity Pathology Pathway interactions Patients Peripheral Plasma Proteins Proteomics Senile Plaques Sorting - Cell Movement Source Specificity Techniques Technology Testing Therapeutic Intervention Validation Western Blotting amyloid pathology base beta secretase beta-site APP cleaving enzyme 1 cost de novo mutation design diagnostic biomarker drug discovery endosome lumen exosome experimental study extracellular in vivo light microscopy mouse model nervous system disorder potential biomarker prodromal Alzheimer&apos s disease receptor single molecule tandem mass spectrometry tau Proteins trafficking

项目摘要

Endosomal dysfunction is a well-accepted cytopathological 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. The current proposal is therefore 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 targeting the AD endosomal trafficking pathway. Genetic and cell biology studies have previously linked retromer -- a multi-modular protein assembly that functions in sorting and trafficking of cargo out of the endosome -- 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. In an effort to characterize defects in the endocytic pathway resulting from retromer dysfunction, and potentially identify biomarkers for AD’s endosomal trafficking defects, we performed a proteomic screen of cerebrospinal fluid (CSF) of VPS35 knock-out (KO) mice and control littermates. Among the proteins found elevated in the CSF of VPS35 deficient mice were well established β-secretase BACE1 substrates including, Amyloid Precursor Protein (APP); Amyloid Beta Precursor Like Proteins 1 and 2 (APLP1 and APLP2); and Neural cell adhesion molecule L1-like protein (CHL1). Two of these proteins --APLP1 and CHL1-- were further validated in mice, and human CSF from cognitively healthy participants and prodromal AD patients. Collectively, our mouse-to-human preliminary results suggest that BACE1 substrates can potentially act as biomarkers of endosomal dysfunction. Relying on these exciting findings, and moving towards the development of a less invasive, more accessible and less costly biomarker; we will explore peripheral exosomal APLP1 as a biomarker of endosomal dysfunction; one of the earliest cytopathological features of AD. Completion of this study will provide initial evidence that an exosome-based plasma test could be diagnostic for the earliest stages of AD.

内体功能障碍是阿尔茨海默病（AD）中公认的细胞病理学特征。然而，目前仍缺乏反映内体交通缺陷的生物标志物，目前的成像和脑脊液 (CSF) AD 生物标志物主要集中于该疾病的组织病理学，即与神经原纤维缠结和淀粉样斑块相关的生物标志物。扩大这一重点，开发 AD 的“细胞生物学”生物标志物，这种生物标志物可能会加速药物的发现，因为目前正在开发针对 AD 内体运输遗传途径的治疗干预措施。细胞生物学研究此前已将retromer（一种多模块蛋白质组装体，其功能是将货物分选并运输出内体）与AD病理联系起来。最值得注意的是retromer的核心蛋白VPS35和retromer的缺陷和罕见突变。受体 SORL1。VPS35 或 SORL1 的耗尽模拟了 AD 的核心细胞病理学，即神经元中核内体的增大，以表征逆转录体功能障碍导致的内吞途径缺陷。为了潜在地识别 AD 内体运输缺陷的生物标志物，我们对 VPS35 敲除 (KO) 小鼠和对照同窝小鼠的脑脊液 (CSF) 进行了蛋白质组学筛选，在 VPS35 缺陷小鼠的脑脊液 (CSF) 中发现升高的蛋白质，其中已确定为 β。 -分泌酶 BACE1 底物，包括淀粉样β前体蛋白 (APP)；淀粉样β前体样蛋白 1 和 2（APLP1 和APLP2）；和神经细胞粘附分子 L1 样蛋白（CHL1），其中两种蛋白——APLP1 和 CHL1——在小鼠以及认知健康参与者和前驱 AD 患者的人类脑脊液中得到了进一步验证。人体初步结果表明，BACE1 底物有可能作为内体功能障碍的生物标志物，并致力于开发一种侵入性更小、更容易获得且成本更低的生物标志物；我们将探索外周外泌体 APLP1 作为内体功能障碍的生物标志物；这项研究的完成将为基于外泌体的血浆测试可以诊断 AD 的早期阶段提供初步证据。

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）

Juvenile CLN3 disease is a lysosomal cholesterol storage disorder: similarities with Niemann-Pick type C disease.

DOI：
10.1016/j.ebiom.2023.104628
发表时间：
2023-06
期刊：
EBIOMEDICINE
影响因子：
11.1
作者：
Chen, Jacinda;Soni, Rajesh Kumar;Xu, Yimeng;Simoes, Sabrina;Liang, Feng-Xia;DeFreitas, Laura;Hwang Jr, Robert;Montesinos, Jorge;Lee, Joseph H.;Area-Gomez, Estela;Nandakumar, Renu;Vardarajan, Badri;Marquer, Catherine
通讯作者：
Marquer, Catherine