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。

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' 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' s disease; receptor; single molecule; tandem mass spectrometry; tau Proteins; trafficking

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）公认的细胞病理学特征。 然而，反映内体运输缺陷的生物标志物仍然缺乏。目前的影像学和脑脊液（CSF）AD生物标志物主要集中在疾病的组织病理学上，即与神经元缠结和淀粉样斑块相关的生物标志物。因此，目前的建议旨在扩大这一重点，以开发AD的“细胞生物学”的生物标志物。这些生物标志物可能会加速药物发现，因为目前正在开发针对AD内体运输途径的治疗干预措施。遗传和细胞生物学研究先前将逆转录酶-一种多模块蛋白质组装体-与AD病理学联系起来，该蛋白质组装体在将货物从内体中分选和运输出来时起作用。最值得注意的是retromer的核心蛋白VPS 35和retromer的受体SORL 1的缺陷和罕见突变。VPS 35或SORL 1的耗尽模拟AD中的核心细胞病理学，即神经元中的扩大的内体。 为了表征由retromer功能障碍引起的内吞途径中的缺陷，并潜在地鉴定AD的内体运输缺陷的生物标志物，我们对VPS 35敲除（KO）小鼠和对照同窝仔的脑脊液（CSF）进行了蛋白质组学筛选。在VPS 35缺陷小鼠的CSF中发现升高的蛋白质中，有充分确定的β-分泌酶BACE 1底物，包括淀粉样前体蛋白（APP）;淀粉样β前体样蛋白1和2（APLP 1和APLP 2）;以及神经细胞粘附分子L1样蛋白（CHL 1）。这些蛋白质中的两种-APLP 1和CHL 1-在小鼠和来自认知健康参与者和前驱AD患者的人CSF中进一步验证。总的来说，我们的小鼠到人的初步结果表明，BACE 1底物可以潜在地作为内体功能障碍的生物标志物。依靠这些令人兴奋的发现，并朝着开发侵入性更小，更容易获得和成本更低的生物标志物的方向发展;我们将探索外周外泌体APLP 1作为内体功能障碍的生物标志物; AD最早的细胞病理学特征之一。这项研究的完成将提供初步证据，表明基于外泌体的血浆测试可以诊断AD的最早阶段。

项目成果

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