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：
C EDWARD DIXON
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
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

来源：
https://reporter.nih.gov/project-details/10063439
关键词：
Acetylation Address Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid beta-Protein Animal Model Astrocytes Attenuated Behavior Therapy Biochemical Biological Assay Brain Brain Injuries Brain-Derived Neurotrophic Factor Cholesterol Chronic Clinical Clinical Trials Cognition Cognitive Therapy Combined Modality Therapy Complement DNA Methylation Data End Point Assay Environment Environmental Risk Factor Epigenetic Process Experimental Animal Model FDA approved Future Genes Genotype Goals Healthcare Systems Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone H3 Human Inflammation Injury Intensive Care Units Intervention Knock-in Mouse Learning Life Link Measurement Measures Memory Microglia Modeling Molecular Mus Nerve Degeneration Neurologic Dysfunctions Neurons Outcome Pathologic Pathology Pathway interactions Personal Satisfaction Pharmaceutical Preparations Pharmacological Treatment Pharmacology Phase Pre-Clinical Model Protein Precursors Proteins Recording of previous events Recovery Rehabilitation therapy Risk Rodent Model Simvastatin Synapses Testing Therapeutic Thinking Transgenic Mice Traumatic Brain Injury Veterans abeta oligomer axon injury behavior test behavioral outcome clinical translation clinically relevant controlled cortical impact dementia risk density disability environmental enrichment for laboratory animals experimental group experimental study histone modification improved improved outcome injured insight mouse model neurobehavioral neurogenesis neuron loss neuropathology novel pleiotropism prevent public health relevance success synaptic function tau Proteins tau aggregation tau-1 therapeutic target

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.

描述：创伤性脑损伤 (TBI) 是退伍军人残疾的常见原因，也是导致阿尔茨海默病 (AD) 痴呆的主要环境危险因素。这两种疾病之间的关键神经病理学联系是大脑中β-淀粉样蛋白 (Aβ) 浓度的增加。环境浓缩 (EE) 是一种非侵入性治疗范例，可以降低大脑中 Aβ 的病理浓度。我们在表达人类 Aβ 的未受伤转基因小鼠（hAβ 敲入小鼠）中进行了试点数据。证明与标准（STD）环境相比，两个月的 EE 暴露基础可降低 Aβ 寡聚物的水平并改善认知，无论单独的 EE 治疗还是与药物治疗相结合，都可以减少脑损伤后 hAβ 的积累和相关病理。 tau 过度磷酸化（突触丢失）和改善神经行为恢复尚不清楚，我们建议在独特的 hAβ 小鼠模型中使用特征明确的控制性皮质冲击（CCI）损伤来解决这个问题。 TBI 诱导的人 Aβ 脑浓度增加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 Aβ 和 p 浓度增加。 -tau、突触丢失和炎症，并改善 hAβ 小鼠的神经行为恢复（目标 1）。第二个主要目标是确定延迟 EE 是否与辛伐他汀治疗联合治疗 CCI。与单独治疗相比，受伤的 hAβ 小鼠将更有效地抑制慢性损伤引起的脑 Aβ 和 p-tau 浓度增加，并改善神经元、突触和神经行为恢复（目标 2）。降低影响，并且是 FDA 批准的药物，具有巨大的转化潜力，因此我们预计所提出的联合治疗范例将最大限度地提高我们的临床前模型的成功和良好恢复的机会。通过检测目标 1 和 2 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。检查在没有 EE 暴露的情况下，组蛋白乙酰化的药理增强（通过给予新型组蛋白脱乙酰酶抑制剂 ITF2357）是否可以实现有益的结果（目的3) 这些研究的结果将a) 深入了解EE 治疗效果背后的新机制途径，这些途径适合药物操作；b) 表征和测试一种新的药物干预措施，以使接受EE（或辛伐他汀治疗）的退伍军人受益。在所有研究中，在对人 Aβ（在 hAβ 小鼠中）、鼠 Aβ（在 C57 中）进行终点检测之前，将评估小鼠的前庭运动功能和学习/记忆能力。表观遗传变化的分析将主要集中在组蛋白 H3 乙酰化上，并通过测量促进恢复的分子来补充。总的来说，这些实验将确定 EE 是否单独使用或与 EE 联合使用。辛伐他汀疗法可以具有双重益处，即改善脑损伤退伍军人的康复并降低发生 AD 病理的风险。