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

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

项目成果

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ELLIOTT Jay MUFSON其他文献

ELLIOTT Jay MUFSON的其他文献

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{{ truncateString('ELLIOTT Jay MUFSON', 18)}}的其他基金

GALANIN REMOLDELING IN THE PROGRESSION OF AD
AD 进展过程中的甘丙肽重塑
  • 批准号:
    6927754
  • 财政年份:
    2005
  • 资助金额:
    $ 184.48万
  • 项目类别:
FOREBRAIN NEUROTROPIC ABNORMALITIES & MILD COGNITIVE IMPAIRMENT IN THE ELDERLY
前脑神经营养异常
  • 批准号:
    6299385
  • 财政年份:
    2000
  • 资助金额:
    $ 184.48万
  • 项目类别:
GALANIN REMODELING IN THE PROGRESSION OF ALZHEIMER'S DISEASE
阿尔茨海默病进展中的甘丙肽重塑
  • 批准号:
    6299298
  • 财政年份:
    2000
  • 资助金额:
    $ 184.48万
  • 项目类别:
GALANIN REMODELING IN THE PROGRESSION OF ALZHEIMER'S DISEASE
阿尔茨海默病进展中的甘丙肽重塑
  • 批准号:
    6098278
  • 财政年份:
    1999
  • 资助金额:
    $ 184.48万
  • 项目类别:
Basic Neuroscience Training in Age-Related Disorders
年龄相关疾病的基础神经科学培训
  • 批准号:
    8451416
  • 财政年份:
    1999
  • 资助金额:
    $ 184.48万
  • 项目类别:
FOREBRAIN NEUROTROPIC ABNORMALITIES & MILD COGNITIVE IMPAIRMENT IN THE ELDERLY
前脑神经营养异常
  • 批准号:
    6098740
  • 财政年份:
    1999
  • 资助金额:
    $ 184.48万
  • 项目类别:
Basic Neuroscience Training in Age-Related Disorders
年龄相关疾病的基础神经科学培训
  • 批准号:
    8874078
  • 财政年份:
    1999
  • 资助金额:
    $ 184.48万
  • 项目类别:
Basic Neuroscience Training in Age-Related Disorders
年龄相关疾病的基础神经科学培训
  • 批准号:
    8658784
  • 财政年份:
    1999
  • 资助金额:
    $ 184.48万
  • 项目类别:
GALANIN REMODELING IN THE PROGRESSION OF ALZHEIMER'S DISEASE
阿尔茨海默病进展中的甘丙肽重塑
  • 批准号:
    6295529
  • 财政年份:
    1999
  • 资助金额:
    $ 184.48万
  • 项目类别:
FOREBRAIN NEUROTROPIC ABNORMALITIES & MILD COGNITIVE IMPAIRMENT IN THE ELDERLY
前脑神经营养异常
  • 批准号:
    6267724
  • 财政年份:
    1998
  • 资助金额:
    $ 184.48万
  • 项目类别:

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