Iron Dyshomeostasis Following Brain Injury: A Novel Mechanism for the Development of Alzheimer-Like Neuropathology and Associated Functional Decline
Abstract
Traumatic brain injury (TBI) is a major health problem across the world, and is predicted to be the major cause of death and disability internationally by 2020. Ten million people are affected by TBI every year due to a variety of causes including vehicular accidents (60%), falls (20%-30%), violence (10%), and sporting/workplace injuries (10%). There is now a compelling body of evidence to indicate that TBI and Alzheimer s disease (AD) are linked. AD is the most common form of dementia in the aged population and is characterized by the accumulation of abnormal protein deposits in the brain that irreparably impair its function and lead to a host of clinical symptoms (including, amongst many other problems, pronounced issues with learning and memory). Several studies have reported that TBI is one of the strongest risk factors for the development of AD, and that AD is accelerated by a history of TBI. Furthermore, the greater the severity of brain injury, the greater the risk of developing AD. In addition, individuals with a history of TBI that occurs relatively close in time to the onset of dementia have a greater risk for the development of functional deficits, and also of a faster rate of decline. Conversely, an examination of the brains of individuals who have experienced a TBI reveals that the proteins that accumulate abnormally in the AD brain are also present and accumulate rapidly after head injury. These pathologies likely contribute to the clinical manifestations that occur in, and are common to, both AD and TBI. Problems, for example, with learning and memory, decision making, anxiety, and depression are all common features likely driven by the degeneration of the brain that occurs following the onset of TBI and AD. As such, there are likely to be common mechanisms that drive the pathology in both conditions. This is the basis for the scientific objective of the proposed project – to explore a mechanism that may be the link between the abnormal brain pathology that is common between AD and TBI and which may then underlie the functional deficits that characterize both conditions. Specifically, there is now compelling evidence that alterations in iron levels in the brain, together with changes in the proteins that regulate iron, are a significant contributor to the development of AD and are also strongly associated with the clinical symptoms. As we have recently demonstrated that iron levels are also profoundly altered following TBI, then we have the potential for a clear link that explains the development of AD-like brain pathology (and potentially also the associated clinical symptom) in the brain following a head trauma. Thus, this project will focus on utilizing cutting edge technologies to specifically address the hypothesis that iron and its regulatory proteins/pathways are altered following TBI, and this creates an environment that precipitates or potentiates the development of AD-like brain pathology and/or injury-specific brain cell changes. These alterations contribute to the functional deficits that occur following head trauma. A secondary hypothesis to be interrogated is that there is an interaction between iron and Apolipoprotein E (ApoE) (an important transporter of things like cholesterol in the body) that further impacts these endpoints post-injury. ApoE is the strongest genetic risk factor for AD, and there is emerging data showing that it specifically interacts with iron and is also involved in brain injury outcome. Thus, iron may be the fundamental link between AD and TBI, and it may also involve ApoE. Understanding these interactions will help us define new therapeutic options in the future that will improve long-term functional outcomes in individuals following a brain injury.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810522
Entities
People
- Paul Adlard
Organizations
- Florey Institute of Neuroscience and Mental Health
- United States Army