Novel Therapeutic Target Identification Through Analysis of Convergent AD and TBI Pathogenic Mechanisms
Abstract
Traumatic brain injury (TBI) is a major cause of mortality and morbidity among both military personnel and the civilian population and is the leading cause of death and disability in the under-45 age group in industrialized countries. Among the Soldiers who survive conflicts in Iraq and Afghanistan, TBI accounts for a larger proportion of their casualties than in any other war in recent US history. Furthermore, among patients evaluated at Walter Reed Hospital, closed head injuries significantly outnumber other penetrating injuries, and although blast injuries have gained much attention in recent years, 84% of TBIs occur in a non-deployed setting involving vehicle crashes, falls, sports, and military training activities (Defense and Veterans Brain Injury Center statistics). The Centers for Disease Control and Prevention estimates that 5.3 million Americans are living with disabilities resulting from TBI. In particular, repetitive mild TBI is now recognized to be a major health concern for both civilian and military populations. These repetitive injuries may result in dementia-like symptoms where the patient may experience memory loss, aggression, confusion, and depression. For many years, TBI has been known to be a risk factor for Alzheimer’s disease (AD) and other neurodegenerative conditions, but the precise nature of how TBI leads to or precipitates AD is not understood. Current treatments for TBI focus on the primary consequences of the injury, such as brain swelling, as the chronic biological consequences of TBI are still mostly unknown. There are very few current clinical trials in the US or even worldwide that are specifically addressing mild TBI, and typically the drugs under investigation were developed for other conditions and have shown very little success thus far, presumably due to the lack of knowledge of the molecular mechanisms which constitute the brains’ secondary response to TBI. These numerous and complex mechanisms may persist for months and even years after the event and naturally are significant contributors to the patient’s outcome. To address this problem, we have used state-of-the-art technology to generate molecular profiles from the brains of mouse models of AD and TBI, at different ages and times post-injury. The AD mouse models have been well characterized in the literature, and the TBI model was developed in-house by our team and has been widely published. Both AD and TBI models recapitulate behavioral and pathological aspects of the human condition that make them relevant and valuable models for studies such as these. We hypothesized that by identifying the TBI-dependent molecular and cellular changes in the brain over time that are coincident with changes in the AD mouse model with age, we would highlight cellular mechanisms that represent critical steps relating TBI to AD. Our data show that in the TBI mouse models, over time, there is significant lipid-related dysfunction and that similar dysfunction is present in the brains of the AD mouse models. Thus, we now propose that treatments that recover the normal brain lipid levels and redress changes in downstream signaling will be effective in blocking the negative consequences of TBI that can ultimately lead to AD. The goal of this proposal is to validate these lipid-related changes as targets for TBI therapeutics. Compounds (both pharmaceuticals/drugs and nutraceuticals/dietary supplements) are currently available that are known to modulate the lipids and cellular mechanisms that we have identified to be of interest. Thus, we plan to first demonstrate in short-term studies that by treating TBI mice with these compounds we are able to modulate the lipid-related profiles towards recovery of the “normal” profile of an uninjured animal. Those compounds showing the greatest potential will then be used to treat TBI mice in a longer study in which the long-term consequences of TBI with or without treatment will be evaluated thro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710638
Entities
People
- Fiona Crawford
Organizations
- Roskamp Institute
- United States Army