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氏病（AD）中受过良好接受的细胞病理学特征。但是，仍然缺乏反映内体交通缺陷的生物标志物。当前的成像和脑脊液（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蛋白斑有关的生物标志物。因此，当前的建议旨在扩大这种重点，以开发AD“细胞生物学”的生物标志物。这种生物标志物可能有可能加速药物发现，因为目前正在开发针对AD内体贩运途径的治疗干预措施。遗传和细胞生物学研究以前已将逆转录器（一种多模块化蛋白质组装联系起来，在货物中的分类和运输中起作用，与AD病理相关。最值得注意的是Rewomer的核心蛋白质VPS35中的缺陷和稀有突变，而反替朗的受体SORL1。 VPS35或SORL1的耗竭模仿AD中的核心细胞病理学，神经元中的内体增加。为了表征逆转录功能障碍导致的内吞途径中的缺陷，并有可能识别AD内体贩运缺陷的生物标志物，我们进行了VPS35敲除（KO）小鼠和控制薄片的蛋白质组织筛查的蛋白质组织筛查。在VPS35缺乏小鼠的CSF中发现升高的蛋白质中，β-分泌酶BACE1底物（包括淀粉样蛋白前体蛋白（APP））已建立了良好的β-分泌酶Bace1底物；淀粉样β前体（如蛋白质1和2）（APLP1和APLP2）；和神经细胞粘附分子L1样蛋白（CHL1）。这些蛋白质中的两种 - APLP1和CHL1-在小鼠中得到了进一步验证，以及来自认知健康参与者和前驱AD患者的人CSF。总的来说，我们的小鼠到人类初步结果表明，BACE1底物可以可能充当内体功能障碍的生物标志物。依靠这些令人兴奋的发现，并朝着开发不太侵入性，更容易获得和成本较低的生物标志物的发展；我们将探索外围外泌体APLP1作为内体功能障碍的生物标志物； AD最早的细胞病理特征之一。这项研究的完成将提供最初的证据，表明基于外泌体的血浆测试可以在AD的最早阶段进行诊断。

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