Endothelial PANNEXIN1-induced inflammation in alzheimer's disease

The National Institute on Aging awarded Tufts Medical Center Parent, Inc. (doing business as Tufts Medical Center) $357,000 under the Aging Research program (CFDA 93.866) on September 1, 2026, to investigate endothelial pannexin1-induced inflammation in Alzheimer's disease. The research tests the hypothesis that amyloid-beta upregulates cerebral endothelial pannexin1 expression, which promotes vascular dysfunction and Alzheimer's disease progression through increased neuroinflammation and blood-brain barrier breakdown. The project will determine the mechanism by which pannexin1-purinergic signaling exacerbates amyloid-beta-induced endothelial dysfunction across two aims. Performance takes place in Boston, Massachusetts, with a period of performance from September 1, 2026 to August 31, 2028.

Abstract

Alzheimer's disease is the most prevalent form of dementia in the elderly and is associated with exacerbated neuroinflammation. A connection between neuroinflammation in alzheimer's disease and vascular dysfunction in both pre-clinical and clinical studies has been identified, but the vascular mechanisms contributing to inflammation in alzheimer's disease remain unclear. PANNEXIN1 (PANX1) channels in cerebral endothelial cells regulate the release of ATP, which subsequently activates downstream purinergic signaling cascades in the vasculature. Purinergic signaling is a critical regulator of neuroinflammation in alzheimer's disease and extracellular nucleotide activation of purinergic receptors has been found to promote alzheimer's disease pathology. We have demonstrated that PANX1 is significantly increased in cerebral endothelial cells from mouse models of alzheimer's disease, human primary brain endothelial cells exposed to increased amyloid-β levels, and in endothelial cells from patients with alzheimer's disease. PANX1 is activated downstream of TNF⍺ resulting in leukocyte adhesion and sepsis-induced peripheral endothelial barrier breakdown. Clinical data demonstrate a positive correlation between serum levels of tnfα and cognitive decline in alzheimer's disease patients. Taken together, these data suggest that endothelial PANX1 may contribute to neuroinflammation in alzheimer's disease; however, the role of endothelial PANX1-mediated inflammation in alzheimer's disease is entirely unknown. We hypothesize that amyloid-β upregulates cerebral endothelial PANX1 expression, which promotes vascular dysfunction and progression of alzheimer's disease via increased neuroinflammation and blood brain barrier (BBB) breakdown. We will test this novel concept in 2 aims. Aim 1 will determine the mechanism by which PANX1- purinergic signaling axis exacerbates amyloid-β-induced endothelial inflammation in vitro utilizing primary human brain endothelial cells. Aim 2 will evaluate the role of endothelial PANX1 in driving ad-associated neuroinflammation and pathology in vivo utilizing the APP/PS1 TG mouse model of alzheimer's disease with and without inducible deletion of endothelial PANX1. Successful completion of our study will identify endothelial PANX1 as a contributor to neuroinflammation in alzheimer's disease, providing a novel target for future therapeutic intervention to reduce vascular dysfunction and improve cognitive function in alzheimer's disease patients.