5HT3 receptors and blood-brain barrier dysfunction in ADRD

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5HT3 receptors and blood-brain barrier dysfunction in ADRD PROJECT SUMMARY/ABSTRACT The exact causes for blood-brain barrier (BBB) dysfunction in cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) is not well known, and the mechanisms of BBB dysfunction remain to be elucidated. The BBB uniqueness is given by the endothelial cells, supported by cells of the neurovascular unit. Alterations in the BBB-endothelium barrier function may lead to increased vascular permeability, extravasation of plasma components, inflammatory responses, and neuronal toxicity in the brain. In CAA, amyloid-β (Aβ) accumulation on brain microvessels has been shown to induce vascular permeability and BBB disruption. Recent findings from our laboratory demonstrated for the first time that serotonin subtype 3 receptor (5HT3R) is expressed in cerebrovascular endothelial cells of postmortem human brain tissues and primary endothelial cells isolated from wild-type mice and TgSwDI, a mouse model of CAA and AD. In addition, our findings demonstrated increased expression of endothelium-5HT3R in CAA; and blocking endothelium-5HT3R with a specific 5HT3R antagonist significantly enhanced the BBB function. In CAA, the impact and the mechanism of increased endothelium- 5HT3R on BBB function are unknown. Our long-term goal is to elucidate the mechanism of BBB dysfunction in CAA and AD-related disorders and identify targets for therapeutics development to restore its function. The objective of this proposal is to clarify the relationship between 5HT3R and BBB dysfunction in CAA and AD. Our central hypothesis is that Aβ-mediated increase of endothelium-5HT3R expression disrupts BBB function. The rationale is that understanding the impact of Aβ-induced endothelium-5HT3R in BBB dysfunction could offer novel targets for therapeutic interventions against ADRD. The central hypothesis will be tested by pursuing two specific aims: 1) Investigate changes in the expression of endothelium-5HT3R in postmortem human brain tissues; and 2) Investigate the effect of changes in endothelium-5HT3R expression/function on the BBB tightness and function using genetic and pharmacological modulation approaches. Upon conclusion, we expect to demonstrate an association between endothelium-5HT3R expression, BBB dysfunction, and CAA. The results will have a significant positive impact because they will identify new insights into BBB dysfunction in CAA and AD and develop new strategies for therapeutic interventions. Future plans are to extend this work in an R01 application to investigate the molecular mechanism(s) for 5HT3R induced expression in the BBB-endothelium in CAA and AD and to develop and test therapeutic drugs that could restore BBB function.