Title : Effect of amyloid-? driven blood brain barrier breakdown on hematopoietic stem cell epigenetic programming in Alzheimer’s
Abstract:
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, neuroinflammation, and blood–brain barrier (BBB) dysfunction, yet the mechanisms linking central pathology to systemic immune dysregulation remain poorly understood. This study proposes that Aβ-induced BBB breakdown promotes the release of endothelial-derived extracellular vesicles (EVs) that traffic to the bone marrow and epigenetically reprogram hematopoietic stem cells (HSCs). Using 5xFAD and wild-type mouse models, we will track EV trafficking, quantify HSC uptake, and assess epigenetic remodeling through single-cell RNA sequencing and ATAC-seq. Functional consequences will be evaluated via HSC transplantation to determine whether EV-mediated reprogramming enhances pro-inflammatory immune cell differentiation, increases neuroinflammation, and further disrupts BBB integrity. We hypothesize that BBB-derived EV signaling establishes a feed-forward neuroimmune loop in which vascular stress drives sustained peripheral immune activation that exacerbates disease progression. Inhibition of endothelial EV release is expected to attenuate HSC reprogramming and partially restore neuroimmune homeostasis. This work introduces a systems-level framework linking BBB dysfunction to peripheral hematopoiesis and identifies EV-mediated signaling as a potential therapeutic target in AD.
