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Default mode network dysfunction in Down Syndrome

唐氏综合症的默认模式网络功能障碍

基本信息

批准号：
10635582
负责人：
ELLIOTT Jay MUFSON
金额：
$ 184.48万
依托单位：
ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10635582
关键词：
Address Age Alternative Splicing Alzheimer&apos s Disease Amyloid beta-Protein Antibodies Apoptotic Autopsy Basic Science CDC2 gene Chromosome 21 Clinical Cytoplasm Data Defect Dementia Development Disease Down Syndrome Down-Regulation Episodic memory Epitopes Event Evolution Exhibits Foundations Gene Expression Gene Expression Alteration Gene Expression Regulation Generations Genes Genetic Genetic Diseases Genetic Models Genetic Predisposition to Disease Genetic Transcription Goals Human Genetics Immunohistochemistry Impaired cognition Intellectual functioning disability Lesion Life Link Maintenance Mediator Memory Messenger RNA Metabolism Modernization Molecular Molecular Profiling Nerve Degeneration Neurofibrillary Tangles Neurons Nuclear Ontology Pathogenesis Pathology Pathway Analysis Pathway interactions Persons Phosphorylation Phosphotransferases Play Population Prevention Principal Investigator Protein Isoforms Protein Splicing Proteins RNA RNA Splicing RNA-Binding Proteins Reporting Role Self Perception Senile Plaques Small Nuclear Ribonucleoproteins Spliceosomes Study models Symptoms Tauopathies Technology Testing Therapeutic Transcript Translations Trisomy U1 Small Nuclear Ribonucleoprotein Validation aged brain tissue case control connectome demented familial Alzheimer disease frontal lobe hippocampal pyramidal neuron human model innovation insight middle age morphometry nano-string network dysfunction neurofibrillary tangle formation neuronal survival non-demented novel novel marker novel strategies novel therapeutics programs resilience tau Proteins tau dysfunction tau mRNA splicing therapy design transcriptome sequencing transcriptomics translational progress trend virtual

项目摘要

Down syndrome (DS), the most common genetic cause of intellectual disability, form the largest population with a genetic predisposition in midlife to develop Alzheimer’s disease (AD). Virtually everyone with DS exhibit neurofibrillary tangles (NFTs) containing-tau and β-amyloid (Aβ) plaques similar to AD by the fourth decade of life, which increase with age. Greater than 70% of people with DS ultimately develop dementia, making this population an excellent naturally-occurring human model for the study of the pathogenesis of dementia with translation to AD. Although NFT pathology is tightly linked to the degree of dementia in both AD and DS compared to Aβ plaques, the cellular mechanisms underlying cognitive decline in DS remain largely unexplored. The goal of this project is to elucidate the molecular and cellular events underlying the selective vulnerability of frontal cortex (FC) and precuneus (PreC) pyramidal neurons. These two interconnected hubs of the default mode network (DMN) are involved in episodic memory and self-awareness and are dysfunctional in AD and DS. We recently reported that people with DS with dementia display a greater number of NFTs in FC pyramidal neurons containing advanced tau pathology compared to those without dementia. Interestingly, we also found that FC NFT-positive neurons in DS with dementia display a different transcriptomic signature compared to non- demented DS, despite having similar FC plaque loads between the DS groups. These findings suggest a key role for tau pathobiology in the onset of dementia in DS. Interestingly, neuronal degeneration is manifested by a confluence of intracellular events leading to alterations in tau mRNA splicing before the onset of clinical symptoms. Recent evidence demonstrated that mislocalized splicing of U1 small nuclear ribonucleoproteins (snRNPs) are associated with NFTs in sporadic and familial AD and DS, but not other tauopathies. We now report greater defects in splicing proteins, particularly those associated with alternative splicing of tau, that occur in the more advanced stages of NFT development in the FC in DS with dementia compared to those without dementia. In this project, we will investigate the molecular pathobiology of selectively vulnerable DMN neurons in people with DS with and without dementia using conceptually and technically innovative approaches: splicing antibodies during the post-translational progression of tau evolution, single population microarray and RNA transcriptomics, combined with functional gene pathway analysis. This proposal expects to lay the foundation for a wide range of potential interventions for the design of novel drugs and biomarkers for the prevention of dementia in DS with translation to AD.

唐氏综合症（DS）是智力残疾最常见的遗传原因，构成了最大的人口