Molecular and cellular underpinnings of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC)

边缘系统主导的年龄相关 TDP-43 脑病神经病理学变化 (LATE-NC) 的分子和细胞基础

• 批准号: 10739186
• 负责人: Hyun-Sik Yang
• 金额: $ 129.6万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739186
• 关键词: Accounting; Affect; Aged, 80 and over; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amygdaloid structure; Amyloid beta-Protein; Astrocytes; Autophagocytosis; Autopsy; Binding Proteins; Biological Assay; Biological Models; Brain; Brain Diseases; Brain region; Cell Nucleus; Cells; Cerebrovascular Disorders; Chromatin; Communities; DNA-Binding Proteins; Data; Dementia; Diagnosis; Disease; Disease model; Elderly; Encephalopathies; Ensure; Event; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Human; In Vitro; Knowledge; Maps; Mediation; Membrane; Memory; Messenger RNA; Metabolism; Modeling; Molecular; Multiomic Data; Nerve Degeneration; Oligodendroglia; Outcome; Participant; Pathology; Pathway interactions; Patients; Persons; Population; Process; Proteins; Proteomics; Public Health; RNA; RNA metabolism; RNA-Binding Proteins; Recommendation; Repression; Research; Research Project Grants; Sampling; Small Nuclear RNA; Statistical Models; Synapses; Systems Development; Testing; Tissues; Transcript; Transposase; United States; United States National Institutes of Health; age related; biomarker discovery; biomarker identification; candidate marker; causal model; cell type; comorbidity; diagnostic biomarker; epigenome; frontal lobe; genetic association; human data; improved; in vivo; limbic-predominant age-related TDP-43 encephalopathy; multiple omics; myelination; neuron loss; neuropathology; prevent; protein TDP-43; protein biomarkers; proteomic signature; religious order study; response; risk variant; sex; symposium; targeted biomarker; targeted treatment; tau Proteins; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT LATE-NC (limbic-predominant age-related transactive response DNA-binding protein of 43 kDa [TDP-43] encephalopathy neuropathological change), a recently recognized form of TDP-43 proteinopathy, is the third most impactful cause of dementia following Alzheimer’s disease neuropathologic change (ADNC) and cerebrovascular disease, accounting for 15-20% of all dementia cases in older adults. Genetic association studies by our group and others revealed unique, LATE-NC-specific risk loci as well as those shared with other common dementia-causing proteinopathies. A transcriptomic study from our group implicated endo-lysosomal dysregulation as a crucial pathophysiologic process underlying LATE-NC. However, molecular and cellular underpinnings of LATE-NC remain largely unknown: we do not even have the knowledge to develop in vitro/in vivo disease models or nominate target pathways, and as a result, we cannot diagnose, treat, or prevent LATE-NC in living persons yet. Defining molecular and cellular changes underlying LATE-NC is a prerequisite to developing translatable in vitro/in vivo disease models and identifying biomarker/therapeutic targets. This critical knowledge gap has been acknowledged by the NIH AD-Related Dementias (ADRD) Summit in 2022, which made a high-priority recommendation to investigate molecular changes associated with LATE-NC. Therefore, this proposal aims to define the transcriptomic, proteomic, and cellular underpinnings of LATE-NC in the human amygdala, the brain region where LATE-NC is thought to originate. Our central hypothesis is that, in the amygdala, endo-lysosomal dysregulation, altered RNA metabolism, glial dysfunction, and neuronal loss underlie LATE-NC pathophysiology. To test the central hypothesis, we propose to generate and analyze transcriptomic, proteomic, and single-nucleus multiome (transcriptome and chromatin accessibility) data from the post-mortem amygdala samples from the extensively characterized Religious Orders Study and Rush Memory and Aging Project participants (n=480). We will pursue the following three specific aims: First, we will determine the transcriptomic underpinnings of LATE-NC. Second, we will identify the proteomic signature of LATE-NC. Third, we will define the single-cell landscape of LATE-NC. We will use statistical modeling approaches to infer causal relationships. We will consider sex-specific effects and the confounding effect of comorbid ADNC pathology throughout the study. The expected outcomes of this project will nominate protein biomarker targets and define plausible upstream and downstream events of LATE-NC. These results will guide our future studies to develop in vitro and possibly in vivo LATE-NC models and, eventually, targeted therapeutics. The large-scale amygdala multi-omic data will be broadly shared with the scientific community to support numerous ADRD research projects, ensuring a significant lasting impact in neurodegeneration research far beyond this proposal. Therefore, this project has the potential to fundamentally improve our ability to diagnose, treat, and ultimately prevent dementia, including LATE.

项目总结/文摘