Investigate the utility of APLP1 as an endosomal biomarker for Alzheimer's Disease in Down Syndrome

研究 APLP1 作为唐氏综合症阿尔茨海默氏病内体生物标志物的效用

• 批准号: 10727134
• 负责人: Sabrina Alves Simoes Spassov
• 金额: $ 45.24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727134
• 关键词: APLP1 gene; APLP2 gene; Acceleration; Address; Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Behavior assessment; Biological Assay; Biological Markers; Birth; Cellular biology; Cerebrospinal Fluid; Characteristics; Clinical; Cognitive; Correlative Study; Defect; Deposition; Detection; Development; Diagnostic; Disease; Disease Progression; Down Syndrome; Early Endosome; Electron Microscopy; Endosomes; Functional disorder; Future; General Population; Genetic; Goals; Histopathology; Human; Immunohistochemistry; Impaired cognition; Individual; Knockout Mice; Late Onset Alzheimer Disease; Linear Models; Link; Memory; Mus; N-terminal; Nerve Degeneration; Neural Cell Adhesion Molecule L1; Neurofibrillary Tangles; Neurons; Participant; Pathologic; Pathology; Pathway interactions; Patients; Persons; Plasma; Population; Prosencephalon; Protein Fragment; Proteins; Proteomics; Sampling; Senile Plaques; Siblings; Synapses; Technology; Testing; Therapeutic Intervention; Therapeutic Trials; Validation; Western Blotting; beta-site APP cleaving enzyme 1; brain tissue; candidate marker; conditional knockout; design; drug discovery; early detection biomarkers; experimental study; in vivo; insight; mouse Ts65Dn; mouse model; neuroimaging; neuropathology; potential biomarker; prevent; prodromal Alzheimer' s disease; single molecule; tau Proteins; tau-1; trafficking; trial design

SUMMARY Genetic and cell biology studies have identified endosomal trafficking as a key cytopathological pathway in both Down Syndrome (DS) and Alzheimer’s disease (AD). However, biomarkers reflecting endosomal traffic defects are still lacking. Current neuroimaging and cerebrospinal fluid (CSF) biomarkers assessed in individuals with DS primarily focus on the histopathology of AD—that is, biomarkers linked to neurofibrillary tangles and amyloid plaques. This proposal is thus designed to expand this focus to develop and validate new biomarkers of the ‘cell biology’ of AD in DS, focusing on endosomal dysfunction, the earliest neuropathological alteration yet to be identified in individuals with DS, preceding amyloid plaques and tau pathology. Such biomarkers would have the potential to accelerate drug discovery, as therapeutic interventions currently being developed for the general population, targeting the AD endosomal trafficking pathway, could also greatly benefit the DS population. In a recent effort to identify new biomarkers for the endosomal trafficking defects in AD, and potentially AD in people with DS, we performed a CSF proteomic screen of a conditional knock out (KO) mouse showing endosomal trafficking defects, in which the VPS35 protein was selectively depleted in forebrain neurons. Among the proteins found elevated in the CSF of VPS35 KO mice relative to control littermates were well established n- terminal fragments of 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 protein fragments -- n-APLP1 and n-CHL1-- were further validated in human CSF from cognitively healthy participants and patients with prodromal AD. Collectively, our mouse-to-human studies suggest BACE1 substrates as potential biomarkers of endosomal dysfunction, a cytopathological characteristic of early stages of AD. Relying on these exciting findings, and since endosomal abnormalities are detected in people with DS decades before any classical AD neuropathology develops, we hypothesize that these endosomal biomarker candidates can also hold potential as biomarkers for the early detection of AD in individuals with DS. The overarching goal of this proposal is thus to focus on one of these candidates – n-APLP1 – and to investigate its potential as an early biomarker of endosomal dysfunction for AD. Completion of this study will provide initial evidence that n-APLP1 can act as the earliest biomarker for the detection and tracking of AD progression in people with DS. Moreover, development of such biomarker would support future therapeutic trials specifically designed to prevent and treat endosomal trafficking dysfunction in AD that could benefit the DS population.

摘要 遗传学和细胞生物学研究已确定内体转运是一种关键的细胞病理途径 在唐氏综合症(DS)和阿尔茨海默病(AD)中都存在。然而，反映内体交通的生物标记物 缺陷仍然存在。目前在个体中评估的神经影像和脑脊液(CSF)生物标志物 DS主要关注AD的组织病理学--即与神经原纤维缠结和 淀粉样斑块。因此，该提案旨在扩大这一重点，以开发和验证新的生物标志物 阿尔茨海默病在DS中的细胞生物学，专注于内体功能障碍，这是迄今为止最早的神经病理改变 在患有DS、先前的淀粉样斑块和tau病理的个体中被识别。这样的生物标志物会有 加速药物发现的潜力，因为目前正在为一般患者开发治疗干预措施 以AD内体转运途径为靶点的人群也可以极大地受益于DS人群。 在最近的一项努力中，为AD的内体运输缺陷识别新的生物标记物，并可能 在DS患者中，我们对条件基因敲除(KO)小鼠进行了脑脊液蛋白质组筛查，结果显示 内体转运缺陷，其中VPS35蛋白在前脑神经元中被选择性地耗尽。其中 与对照仔鼠相比，VPS35KO小鼠脑脊液中发现的蛋白质升高是非常确定的。 BACE1底物的末端片段，包括淀粉样前体蛋白(APP)；淀粉样β前体 类蛋白1和2(APLP1和APLP2)；以及神经细胞黏附分子L1类蛋白(CHL1)。其中两个 这些蛋白质片段-n-APLP1和n-CHL1-在认知健康的人脑脊液中进一步得到验证 受试者和先兆AD患者。总的来说，我们从老鼠到人类的研究表明，BACE1 底物作为内体功能障碍的潜在生物标志物，这是早期的细胞病理学特征 广告。根据这些令人兴奋的发现，由于在DS患者中检测到内体异常 在任何经典的阿尔茨海默病神经病理学发展之前的几十年，我们假设这些内体生物标志物 候选人还可以作为生物标志物，在患有DS的个体中早期检测AD。 因此，这项提案的首要目标是将重点放在这些候选者之一--n-APLP1-- 并探讨其作为AD患者内体功能障碍的早期生物标志物的可能性。完成 这项研究将提供初步证据，证明n-APLP1可以作为检测的最早生物标志物 以及追踪DS患者的AD进展情况。此外，这种生物标记物的开发将 支持未来专门为预防和治疗内体贩运而设计的治疗试验 阿尔茨海默病的功能障碍，可能使DS人群受益。