Gut microbiota depletion modulates cerebrovascular dysfunction in Alzheimer’s disease via IL-17 A/Act1-driven pyroptosis-associated pericyte injury

Cerebrovascular dysfunction is an early hallmark of Alzheimer’s disease (AD), yet the upstream drivers linking peripheral immunity to neurovascular injury remain elusive. The gut microbiota has emerged as a critical regulator of systemic immunity, but whether and how microbiota-driven immune signals impair the neurovascular unit remains poorly understand. Using APP/PS1 mice and primary mouse cerebral pericytes, we investigated the effects of gut microbiota depletion and IL-17 A neutralization on AD-associated neurovascular dysfunction. We integrated flow cytometry of meningeal immunity, Evans Blue assays for blood-brain barrier (BBB) integrity, and molecular analyses of pyroptosis-associated pericyte injury and neurotrophic signaling. Gut microbiota depletion significantly attenuated cerebrovascular rarefaction, restored pericyte coverage, and rescued BBB leakage in APP/PS1 mice. These vascular improvements were accompanied by marked reductions in systemic IL-17 A levels and meningeal CD4 + IL-17 A + T cell accumulation. Mechanistically, IL-17 A induced pyroptosis-associated pericyte injury through an IL-17RA/Act1 dependent signaling cascade involving the NLRP3 inflammasome. Concurrently, IL-17 A signaling suppressed the CREB/BDNF trophic axis, further compromising pericyte survival. Pharmacological neutralization of IL-17 A recapitulated the neurovascular and cognitive protection observed with microbiota depletion, whereas combined interventions yielded no additive effects. Our results identify gut microbiota-associated IL-17 A signaling as a contributor to pyroptosis-associated pericyte injury and neurovascular unit dysfunction in AD, highlighting this pathway as a potential therapeutic target for early intervention.