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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.