Pulsed laser therapy in an asymptomatic head injury-accelerated Alzheimer's model

Abstract Traumatic brain injury (TBI) is a significant cause of death and disability in the US. The true extent of TBI may be underestimated, with many cases of asymptomatic TBI going undiagnosed, often referred to as a “silent epidemic.” Recent meta-analyses suggest that head injuries increase the risk of dementia and Alzheimer's

disease (AD). As a result, there is an urgent need for strategies to prevent TBI-induced AD dementia and research to uncover its underlying mechanisms. Notably, TBI often results in significant damage to the blood-brain barrier (BBB). Even a single mild TBI can lead to persistent BBB breakdown. Additionally, TBI

commonly damages brain microvascular endothelial cells, crucial components of the BBB. Both cerebrovascular dysfunction and BBB damage are early and critical events in AD pathology. Therefore, it is reasonable to hypothesize that TBI-related BBB breakdown may contribute to the aggravated progression of AD.

However, the causal relationship between disrupted endothelial cell and BBB function caused by TBI and the accelerated AD progression remains unclear. In this study, we propose noninvasive laser therapy as a potential therapeutic approach for brain protection in a mild closed-head injury (CHI)-accelerated AD dementia model. To

test our overall hypothesis, Aim 1 will determine the impact of pulsed laser therapy on CHI-accelerated AD pathogenesis in a novel AD rat model and elucidate the role of DDR-senescent signaling in this process. Aim 2 will test the hypothesis that endothelial cell senescence and BBB damage represent significant pathological

links between TBI and AD. Additionally, we will establish a mechanistic angle to determine whether H2S signaling molecule is associated with laser protection in CHI-AD. Aim 3 will examine the hypothesis that laser therapy can target ion-containing cystathionine-β-synthase/H2S system to enhance DNA/vascular repair and

functional neurovascular coupling during CHI-AD pathogenesis. The proposed research is innovative both technically and mechanistically. The studies have the potential for profound impact as they aim to elucidate the mechanisms underlying TBI-accelerated AD progression, identify novel target for laser therapy in CHI-AD, and

assess the efficacy and utility of this emerging noninvasive therapy in the early stages of TBI-AD progression.