Multifunctional rehabilitative therapy to reduce Alzheimer pathology after TBI

 描述： 颅脑损伤是导致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。这两种疾病之间的一个关键神经病理联系，大脑淀粉样蛋白-β(Aβ)浓度增加，也是治疗的目标。环境浓缩(EE)是一种非侵入性治疗模式，可以降低Aβ在大脑中的病理浓度。我们在未受伤的表达人Aβ的转基因小鼠(HAβ敲入小鼠)上的试点数据表明，与标准(性传播疾病)环境相比，两个月的EE暴露降低了Aβ寡聚体的基础水平，并改善了认知。目前尚不清楚EE单独治疗或联合药物治疗是否能减少脑损伤后HA-β的积聚和相关的病理(tau蛋白过度磷酸化、突触丢失)，并改善神经行为恢复。我们建议使用具有良好特征的受控皮质撞击(CCI)损伤来解决这个问题，在独特的HAβ小鼠模型中，脑创伤诱导的人Aβ浓度增加。辛伐他汀具有促进康复和降低Aβ的作用，是美国食品和药物管理局批准的具有巨大翻译潜力的药物，因此我们预计拟议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。这些研究的结果将a)提供对EE治疗效果的潜在的新的机制途径的洞察，并且b)描述和测试一种新的药物干预措施，以使EE(或辛伐他汀治疗)对其不太可行的退伍军人受益。在所有研究中，在进行人类Aβ(在HAβ小鼠中)、小鼠Aβ(在C57小鼠中)和p-tau(两种基因型)、轴突损伤、突触密度、小胶质细胞/星形胶质细胞激活和神经元丢失的终点分析之前，将对小鼠的前庭运动功能和学习/记忆进行评估。表观遗传学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。神经营养因子、神经生长因子、分泌的APPα)、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生AD病理的风险而具有双重益处。

 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.