6th Edition of Neurology World Conference 2026

Abstract

Background: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) accumulation, blood–brain barrier (BBB) dysfunction, and neuroinflammation. Emerging evidence suggests that peripheral immune systems contribute to disease progression, yet the mechanisms linking BBB disruption to systemic immune reprogramming remain unclear. Extracellular vesicles (EVs) derived from BBB endothelial cells may act as long-distance signaling mediators between the brain and bone marrow, influencing hematopoietic stem cell (HSC) behavior. Methods: This study employs transgenic 5xFAD and wild-type mouse models across four experimental groups to evaluate the role of BBB-derived EVs in mediating brain–bone marrow communication. Endothelial-specific EV secretion will be inhibited via conditional Rab27a/b silencing. BBB permeability will be assessed using intravital imaging and tracer leakage assays. EV trafficking will be tracked using fluorescent labeling and flow cytometry. HSCs (LSK population) will be isolated and analyzed using single-cell RNA sequencing and ATAC-seq to evaluate transcriptional and epigenetic changes. Functional consequences will be assessed through HSC transplantation into recipient mice, followed by measurement of neuroinflammatory markers and BBB integrity. Reversibility will be evaluated after restoration of normal conditions. Hypothesized Results: Aβ-induced BBB disruption is expected to increase EV trafficking to bone marrow HSCs, resulting in elevated EV uptake and epigenetic remodeling characterized by increased chromatin accessibility in inflammatory pathways. HSCs exposed to BBB-derived EVs are anticipated to promote heightened neuroinflammation and BBB permeability upon transplantation into recipient mice, supporting a causal feedback loop. Inhibition of endothelial EV release is expected to attenuate these effects, partially restoring neuroimmune homeostasis, though not fully reversing pathology due to persistent amyloid burden. Conclusions: This study proposes a novel mechanism in which Aβ-driven BBB dysfunction promotes EV-mediated epigenetic reprogramming of HSCs, establishing a feed-forward brain–bone marrow signaling axis that exacerbates neuroinflammation. Targeting EV-mediated communication may represent a potential therapeutic strategy to restore neuroimmune balance and slow AD progression.