Frontiers in Cell and Developmental Biology · Nov 10, 2026
Brain-derived extracellular vesicles and marrow stromal regulation: implications for skeletal fragility in Alzheimer's disease and aging
By Qiuhan Chen, Hongfei Wang, Liangyu Shi et al.
Cognitive impairment is associated with bone loss and fracture, raising the question of how neural disease influences the cells that maintain the skeleton. Brain-derived extracellular vesicles (EVs) provide a route through which neural state can alter marrow stromal activity. This Review compares the underlying recipient mechanisms with stromal lineage, aging and niche biology. In Alzheimer's disease (AD) models, brain EV-associated miR-483-5p is linked to reduced osteogenic growth-factor support. In aging mice, neuronal WD repeat and FYVE domain-containing protein 1 (WDFY1) changes retromer-dependent protein trafficking. Injury-associated neural miRNAs and neural stem-cell EV-associated perilipin 5 provide contrasting examples of osteoprogenitor stimulation and metabolic support. These findings connect neural source states to different cellular operations that can converge on bone formation. We distinguish changes in differentiation potential, cell abundance, protein routing and lipid utilization, and examine how vascular and inflammatory niche states shape their tissue consequences. Human cohort associations, circulating EV activity and source-selective animal interventions contribute complementary evidence. We propose that marrow regenerative capacity, assessed before intervention by task-relevant measures of progenitor abundance, function or niche support, modifies the bone-formation benefit attributable to reducing adverse neural EV exposure. A prospective dose–response design can test whether recipients with preserved capacity show greater formation gains after interruption of adverse cargo activity, while measuring delivery and early target responses. We outline tests of this hypothesis and relate molecular profiling to skeletal outcomes. A mechanistic account of source, functional cargo delivery and recipient capacity can guide evaluation of the brain–bone axis in cognitive impairment-associated fragility.