Thursday, November 21, 2024
11/21/2024
Traumatic brain injury (TBI) is a condition in which normal brain function is impaired by an external force. TBI is estimated to affect ~69 million people worldwide each year. Mild TBI’s are the most common form of brain injury (~70-90% of all cases), characterized by little-to-no time unconscious and minimal observable deficits immediately post-injury. Mild brain injuries are commonly attributed to participation in contact sports (e.g. boxing, football, soccer, hockey), military service, and as a result of intimate partner violence. Even mild TBI, especially following repeated injuries, has devastating acute and long-term consequences, including an increased risk of stroke and dementia. Given the clear evidence that TBI increases the risk of dementia in later life, it is of great interest to determine the mechanisms that drive the relationship between different types of TBIs and various dementia-associated neuropathologies, so that targets for intervention may be identified. Repetitive mild TBI has been most notably associated with chronic traumatic encephalopathy (a tauopathy), though some evidence suggests it may also contribute to Alzheimer’s and other neurodegenerative conditions. However, less is known about whether cerebral amyloid angiopathy (CAA) may also be a mechanism linking TBI to dementia. CAA is the accumulation of amyloid protein (most commonly beta-amyloid, associated with Alzheimer's disease) within the cerebral vasculature, contributing to increased risk of dementia [both vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease], as well as ischemic and hemorrhagic stroke. Increased levels of CAA are observed in former athletes, who tend to have a history of repetitive mild brain injuries. Experimental designs using animal models are needed to determine whether and how repetitive mild TBI influences the initiation and progression of CAA and related pathology. Here, we will subject Tg-SwDI mice (a transgenic mouse model of CAA) to repetitive mild TBI (1x/day for 5 consecutive days) starting at ~2 months of age. This age is roughly equivalent to late adolescence/young adulthood, when TBI is most common, and is prior to the onset of significant CAA pathology and cognitive impairment in this strain. We will then determine whether cognitive-behavioral deficits and neuropathology are altered at two time-points post-TBI (short-term: 7 days and longer-term: 3 months). Additionally, we will investigate whether biological sex moderates the relationship between repetitive mild TBI and CAA-associated outcomes. Our long-term goal is to identify mechanisms linking TBI and increased dementia risk, which may in turn reveal novel targets for treatment.
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