: 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-? (A?), is also a therapeutic target. Environmental enrichment (EE) is a non-invasive therapeutic paradigm that can reduce pathological concentrations of A? in the brain. Our pilot data in uninjured genetically modified mice expressing human A? (hA? knock-in mice) demonstrate that compared to standard (STD) environment, two months of EE exposure reduces basal levels of A? oligomers and improves cognition. Whether EE therapy, alone or in combination with pharmacological treatment, can reduce post-injury accumulation of brain hA? 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 hA? mouse model of TBI-induced increases in brain concentrations of human A?. 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 A? and p-tau, synapse loss, and inflammation, and improve neurobehavioral recovery in hA? mice (Aim 1). The second major goal is to determine if delayed EE combined with simvastatin therapy in CCI injured hA? mice will be more effective in suppressing chronic injury-evoked increases in brain A? and p-tau concentrations, and improving neuronal, synaptic, and neurobehavioral recovery compared to either therapy alone (Aim 2). Simvastatin has recovery-promoting and A?-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 A? (in hA? mice), murine A? (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 APP?), 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.
Traumatic brain injury (TBI) is a major cause of disability, yet therapies for improved recovery remain undiscovered. Veterans with a history of severe TBI have difficulties thinking and remembering and are at an increased risk for developing Alzheimer's disease (AD) later in life. In a unique experimental animal model, we will see if delayed, long-term, non-invasive rehabilitative therapy using environmental enrichment (EE), alone or combined with simvastatin, a cholesterol lowering drug which helps the injured brain, will improve recovery and reduce brain levels of toxic proteins that accumulate after TBI. We will also examine a novel, gene- regulating mechanism underlying the effects of EE/simvastatin therapy. These studies will provide critical data to guide future clinical trials using EE and simvastatin to enhance rehabilitation after TBI and reduce risk of developing AD. The proposed therapies have a high chance to improve well-being of brain injured Veterans and reduce the burden on the VA healthcare system.
|Ikonomovic, Milos D; Mi, Zhiping; Abrahamson, Eric E (2017) Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders. Ageing Res Rev 34:51-63|