Systemic young blood plasma attenuates neuroinflammatory and neurovascular alterations in R6/2 Huntington’s disease mice

Neuroinflammation and blood–brain barrier (BBB) disruption are increasingly implicated in Huntington’s disease (HD) pathophysiology. Microglial activation, mitochondrial dysfunction, and neurovascular instability are closely associated with mutant huntingtin (mHTT)-mediated neuronal vulnerability. Systemic factors present in young blood have been implicated in modulating inflammatory tone and vascular integrity; however, their impact on HD-associated neuroinflammatory cascades remains incompletely defined. Using the R6/2 transgenic mouse model of HD, we investigated whether systemic infusion of young blood plasma (YBP) modulates neuroinflammatory and neurovascular pathology. R6/2 mice received intravenous YBP from 8 to 12 weeks of age. Microglial responses (Iba1), BBB integrity (claudin-5, occludin, laminin, CD13), mitochondrial signaling (PGC-1α, p-AKT/AKT, p-CREB/CREB), apoptotic markers, and mHTT aggregation (EM48) were assessed. Behavioral performance was evaluated using novel object recognition and rotarod testing. YBP treatment significantly suppressed reduced Iba-1 immunoreactivityin the striatum. Concomitantly, tight junction and basement membrane proteins were upregulated, indicating stabilization of the neurovascular unit. These changes were accompanied by enhanced activation of the AKT–CREB–PGC-1α signaling axis and attenuation of pro-apoptotic signaling. In concordance with these coordinated molecular and inflammatory changes, YBP infusion was associated with reduced intranuclear mHTT aggregation and delayed cognitive and motor decline. Collectively, these findings suggest that systemic YBP modulates interconnected neuroinflammatory and survival pathways that are linked to improved pathological and functional outcomes. Systemic YBP infusion is associated with coordinated modulation of the neuroinflammatory–neurovascular axis in R6/2 mice. These findings support the concept that circulating systemic factors can influence inflammatory components of HD pathology and may represent a potential adjunctive therapeutic strategy.