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.
 产品说明: 创伤性脑损伤(TBI)是退伍军人残疾的常见原因,也是发展阿尔茨海默病(AD)痴呆的主要环境风险因素。这两种疾病之间的关键神经病理学联系,淀粉样蛋白-β(A β)的脑浓度增加,也是一个治疗靶点。环境富集(EE)是一种非侵入性治疗模式,可以降低脑中A β的病理浓度。我们在表达人A β的未受伤转基因小鼠(hA β基因敲入小鼠)中的试验数据表明,与标准(STD)环境相比,两个月的EE暴露降低了A β寡聚体的基础水平并改善了认知。EE治疗单独或与药物治疗联合是否可以减少脑hA β的损伤后蓄积和相关病理(tau过度磷酸化,突触丢失)并改善神经行为恢复尚不清楚。我们建议在TBI诱导的人A β脑浓度增加的独特hA β小鼠模型中使用充分表征的受控皮质撞击(CCI)损伤来解决这个问题。我们将首先检查临床相关的延迟EE暴露(CCI损伤后2周开始),维持1或3个月是否会抑制TBI诱导的脑A β和p-tau增加、突触丢失和炎症,并改善hA β小鼠的神经行为恢复(目的1)。第二个主要目标是确定与单独治疗相比,延迟EE联合辛伐他汀治疗CCI损伤的hA β小鼠是否能更有效地抑制慢性损伤诱发的脑A β和p-tau浓度增加,并改善神经元、突触和神经行为恢复(目的2)。辛伐他汀具有促进恢复和降低A β的作用,并且是FDA批准的具有巨大转化潜力的药物,因此我们预期所提出的联合治疗范例将在我们的临床前模型中最大化成功和有利恢复的机会。第三,我们建议通过分析目的1和2的实验组中的组蛋白修饰(乙酰化)和DNA甲基化,研究表观遗传因素与TBI诱导的神经病理学/神经功能障碍的相关性以及EE和EE/辛伐他汀治疗的恢复促进作用。我们还将检查在没有EE暴露的情况下,组蛋白乙酰化的药理学增强(通过给予新型组蛋白去乙酰化酶抑制剂ITF 2357)是否可以实现有益的结果(目的3)。这些研究的结果将a)提供对EE治疗作用的潜在新机制途径的深入了解,这些机制途径适合于药理学操作,和B)表征和测试一种新的药理学干预,以使EE(或辛伐他汀治疗)不太可行的退伍军人受益。在所有研究中,在人A β(hA β小鼠)、鼠A β(C57小鼠)和p-tau(两种基因型)、轴突损伤、突触密度、小胶质细胞/星形胶质细胞活化和神经元丢失的终点试验前,将评价小鼠的前庭功能和学习/记忆。表观遗传变化的分析将主要集中在组蛋白H3乙酰化;这些研究将通过测量促进恢复的分子(例如,BDNF、NGF、分泌的APP α)、神经发生的标志物和神经行为恢复。总的来说,这些实验将确定EE单独或与辛伐他汀联合治疗是否可以通过改善脑损伤退伍军人的康复和降低发展AD病理学的风险而具有双重益处。

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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