Tuesday, May 7, 2024
5/7/2024
Abstract Cardiac arrest and stroke are serious health concerns and pressing public health issues in the United States, affecting over a million people every year. However, the severity of the problem is largely underestimated, because a significant portion of patients with asymptomatic cerebral ischemia following cardiac arrest or stroke are unnoticed and undiagnosed, which is often referred to as “silent brain ischemia (SBI)”. As one type of SBI, silent strokes are more common than strokes that cause detected symptoms. The SBI is usually categorized on the basis of a standard neurological exam, which does not cause any disability or symptoms of cognitive decline. Population-bases studies have observed a long-term association between SBI and an increased risk of developing dementia and Alzheimer's disease (AD). Therefore, research study on the strategies to determine the underlying mechanisms and prevent SBI-induced dementia is urgently needed in a society with a growing aged population. Herein, we propose that pulsed laser therapy could effectively protect the SBI brain from developing AD dementia. We have recently demonstrated the beneficial effects of laser therapy in brain injury and neurodegeneration, including global cerebral ischemia (GCI), stroke and AD. In this proposal, we will apply technically innovative approaches to improve the laser’s efficacy that penetrates the brain at sufficient depth, providing further beneficial evidence of laser therapy. In healthy wild type rats that subjected to a short-term 3-min GCI, we were unable to identify any pathological and behavioral changes in long term. However, such a brief ischemic insult could significantly accelerate plaque formation and cognitive decline in the transgenic AD rats. For the first time, the SBI model is combined with the clinically relevant AD rat model to simulate clinical SBI conditions in increasing the incidence of AD dementia. In this proposal, we will test the hypothesis that SBI-induced DNA damage response (DDR) and cellular senescence in the vascular endothelial cells plays a causal role in the pathogenesis of SBI-AD dementia. We hypothesize that ions containing blood hemoglobin exudes through the damaged blood-brain barrier gradually aggregates Aß deposition, which ultimately culminate in neurodegeneration and cognitive impairment in the SBI-AD rats. We will further test the hypothesis that pulsed laser therapy will increase internal levels of hydrogen sulfide, a key gaseous signaling molecule mediating DNA repair and senescent inhibition, which was compromised in the SBI-AD animals. The proposed research is both mechanistically and technically innovative as it will elucidate the causal pathological progression underlying SBI-accelerated AD dementia in a novel AD-like rat model while also identifying novel mechanism for pulsed laser therapy. Therefore, this proposal has valuable clinical novelty for the prevention of SBI-accelerated AD dementia.
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