Multifunctional rehabilitative therapy to reduce Alzheimer pathology after TBI

多功能康复治疗可减少 TBI 后阿尔茨海默病的病理变化

基本信息

  • 批准号:
    10063439
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-04-01 至 2021-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION : Traumatic brain injury (TBI) is a prevalent cause of disability in Veterans and a major environmental risk factor for developing Alzheimer's disease (AD) dementia. A key neuropathological link between the two conditions, increased brain concentration of amyloid-β (Aβ), is also a therapeutic target. Environmental enrichment (EE) is a non-invasive therapeutic paradigm that can reduce pathological concentrations of Aβ in the brain. Our pilot data in uninjured genetically modified mice expressing human Aβ (hAβ knock-in mice) demonstrate that compared to standard (STD) environment, two months of EE exposure reduces basal levels of Aβ oligomers and improves cognition. Whether EE therapy, alone or in combination with pharmacological treatment, can reduce post-injury accumulation of brain hAβ and related pathology (tau hyper-phosphorylation, synaptic loss) and improve neurobehavioral recovery, is unknown. We propose to address this question using well characterized controlled cortical impact (CCI) injury in the unique hAβ mouse model of TBI-induced increases in brain concentrations of human Aβ. We will first examine if clinically-relevant, delayed EE exposure (initiated 2 weeks after CCI injury), maintained for either 1 or 3 months will suppress TBI-induced increases in brain Aβ and p-tau, synapse loss, and inflammation, and improve neurobehavioral recovery in hAβ mice (Aim 1). The second major goal is to determine if delayed EE combined with simvastatin therapy in CCI injured hAβ mice will be more effective in suppressing chronic injury-evoked increases in brain Aβ and p-tau concentrations, and improving neuronal, synaptic, and neurobehavioral recovery compared to either therapy alone (Aim 2). Simvastatin has recovery-promoting and Aβ-lowering effects, and is an FDA approved drug with great translational potential thus we expect that the proposed combination therapy paradigm will maximize the chances of success and favorable recovery in our preclinical model. Thirdly, we propose to investigate the correlation of epigenetic factors with TBI-induced neuropathology/neurological dysfunction and the recovery promoting effects of EE and EE/simvastatin therapy, by assaying histone modifications (acetylation) and DNA methylation in experimental groups from Aims 1 and 2. We will also examine if in the absence of EE exposure, pharmacological enhancement of histone acetylation (through administration of the novel histone deacetylase inhibitor ITF2357) can achieve beneficial outcomes (Aim 3). The results of these studies will a) provide insight into novel mechanistic pathways underlying the effects of EE therapy that are amenable to pharmacological manipulation and b) characterize and test a novel pharmacological intervention to benefit Veterans for whom EE (or simvastatin therapy) is less feasible. In all studies, mice will be evaluated for vestibulomotor function and learning/memory prior to the endpoint assays of human Aβ (in hAβ mice), murine Aβ (in C57 mice) and p- tau (both genotypes), axonal damage, synapse density, microglia/astrocyte activation, and neuronal loss. Analyses of epigenetic changes will focus primarily on histone H3 acetylation; these studies will be complemented by measuring recovery-promoting molecules (eg. BDNF, NGF, secreted APPα), markers of neurogenesis, and neurobehavioral recovery. Collectively, these experiments will determine if EE, alone or combined with simvastatin therapy, can be of dual benefit by both improving the rehabilitation and reducing the risk of developing AD pathology in brain injured Veterans.


项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Differential Regional Responses in Soluble Monomeric Alpha Synuclein Abundance Following Traumatic Brain Injury.
  • DOI:
    10.1007/s12035-020-02123-w
  • 发表时间:
    2021-01
  • 期刊:
  • 影响因子:
    5.1
  • 作者:
    Carlson SW;Yan HQ;Li Y;Henchir J;Ma X;Young MS;Ikonomovic MD;Dixon CE
  • 通讯作者:
    Dixon CE
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C EDWARD DIXON其他文献

C EDWARD DIXON的其他文献

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{{ truncateString('C EDWARD DIXON', 18)}}的其他基金

Targeting Cholinergic Deficits with Retinoic Acid after TBI
使用视黄酸治疗 TBI 后的胆碱能缺陷
  • 批准号:
    10741924
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
PRECISE-TBI: PRE Clinical lnteragency research resourcE-TBI
PRECISE-TBI:PRE 临床跨机构研究资源E-TBI
  • 批准号:
    10935621
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Neurogranin and Traumatic Brain Injury
神经粒蛋白和创伤性脑损伤
  • 批准号:
    10254474
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Neurogranin and Traumatic Brain Injury
神经粒蛋白和创伤性脑损伤
  • 批准号:
    10512044
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
PRECISE-TBI: PRE Clinical lnteragency research resourcE-TBI
PRECISE-TBI:PRE 临床跨机构研究资源E-TBI
  • 批准号:
    10378331
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
PRECISE-TBI: PRE Clinical lnteragency research resourcE-TBI
PRECISE-TBI:PRE 临床跨机构研究资源E-TBI
  • 批准号:
    10620688
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Connectome Analysis of the Nigrostriatal Neuronal Tract after Blast TBI
冲击波 TBI 后黑质纹状体神经元束的连接组分析
  • 批准号:
    10015797
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Structural and Functional Dysconnectivity in Dopamine/Acetylcholine Circuitry in Repetitive Mild TBI
重复性轻度 TBI 中多巴胺/乙酰胆碱回路的结构和功能脱节
  • 批准号:
    9916055
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Role of UCHL1 in Axonal Injury and Recovery after TBI
UCHL1 在 TBI 后轴突损伤和恢复中的作用
  • 批准号:
    10199060
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Chronic Lithium Therapy for Traumatic Brain Injury
慢性锂盐治疗创伤性脑损伤
  • 批准号:
    9260706
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:

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