Traumatic Brain Injury: Degenerative Mechanisms, Phenserine Treatment and Exosome Biomarkers of Response

Traumatic brain injury (TBI) is a leading cause of death and long-term physical or mental condition disability in the developed world. By 2020 TBI will comprise the third largest portion of the global disease. Within the first year after injury, 70-90% of patients continue to manifest prolonged and constantly permanent neurocognitive dysfunctions. Recently, the emerging evidence indicates that this process of TBI can lead to early onset of dementia. TBI is a strong environmental risk factor for development of Alzheimer’s disease (AD). Newly gene expression studies have demonstrated upregulation of pathways leading to AD and Parkinson’s disease induced by even mild TBI. Second phase of TBI involves cascades of biological processes may be reversible and is imperative to understand the biological cascades as a major potential therapeutic target. The clinical experimental drug Phenserine as an agent that can inhibit an extensive range of pathological mechanisms used in TBI and neurodegeneration. The pharmacological benefits of Phenserine include 1. antiinflammatory activities; 2. suppression of glutamate induced excitotoxicity; 3. protection against oxidative stress; 4. inhibition of APP synthesis; 5. augmentation of neurogenesis; 6. counters cholinergic losses from nucleus Basailis of Meynert injuries; 7. preservation of visual and spatial memory in TBI mice; 8. augmenting endogenous antioxidant proteins; 9. reduction of pre-programmed cell death in wild and tg mice after TBI; and 10. protection of neurons from anoxia. Together these data suggest that multiple phenserine-associated actions consolidate this compound's ability to improve cognitive dysfunction caused by TBI, and support the further evaluation of the compound as a therapeutic for TBI and AD. Our lab and collaborative team have extensive experience in characterizing key proteins in pathological cascades to evaluate their potential as biomarkers of neurodegeneration and of treatment response. Exosomes that are enriched for neural (L1CAM) or astrocytic (GLAST) origin have been time-dependently obtained from both animal models of neurodegeneration, as well as from humans. We will evaluate and quantify key proteins within neural- and astrocyte-derived exosomes that we will obtain from plasma samples that can provide direct information about neurodegenerative molecular pathophysiology and drug responses. We propose to examine the hypothesis that TBI injury might lead to the progression of AD neuropathology and cognitive impairment by cross-using and cross-validating TBI and AD transgenic mice. Our study aims are: Aim 1: Evaluation of behavior in CCI-induced TBI micemotor behavior; cognitive behavior Y maze – spatial memoryAim 2: Histology evaluation of TBI injury by Fluoro Jade C staining; contusion volume; immunocytochemistry and biochemistry for markers of neuron numbers, oxidative stress, and apoptotic-related moleculesAim 3: Studies on neuroinflammation evaluation of expression of inflammatory cytokines; evaluation of microglial phenotypeAim 4; Exosome analysis as biomarkers of pathological processes and drug responses to evaluate neuronal expression of TBI-associated proteins longitudinally; to evaluate the levels of APPs, pro-and anti-inflammatory cytokines, such as TNF-α, IL-1 and IL-6, and of IL-10 and TGFβ; to evaluate oxidative stress Aim 5; Evaluation behaviors in AD miceAim 6, 7 and 8: same as study aim 2-4 in AD mice