Small-molecule PCSK9 inhibition enhances BBB amyloid-β clearance and suppresses microglial inflammation in Alzheimer's disease models.

Impaired amyloid-β (Aβ) clearance and chronic neuroinflammation are central drivers of Alzheimer's disease (AD) progression, yet therapeutic strategies targeting these processes remain limited. Proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulates low-density lipoprotein receptor family members, including low-density lipoprotein receptor -related protein 1 (LRP1), a key mediator of blood-brain barrier (BBB) Aβ efflux, and has emerging roles in inflammatory signaling. In this study, to define the therapeutic relevance of PCSK9 inhibition in AD-like pathology, we examined SBC-115,076 in AlCl₃-challenged zebrafish larvae and mechanistically validated its effects using complementary endothelial-microglial in vitro models. SBC-115,076 significantly improved locomotor behavior and sensorimotor responsiveness, reduced Aβ deposition and neuronal apoptosis, and normalized oxidative stress, cholinergic dysfunction, and neuroinflammatory markers in vivo. Mechanistically, SBC-115,076 downregulated endothelial PCSK9 and upregulated LRP1, thereby enhancing Aβ endocytosis, lysosomal trafficking, and selective brain-to-blood efflux across an in vitro BBB model. In parallel, SBC-115,076 suppressed Aβ-induced CD36/TLR4 signaling in microglia, attenuated M1-like activation, promoted M2-like polarization, and reduced pro-inflammatory cytokine release. Collectively, these findings demonstrate that small-molecule PCSK9 inhibition ameliorates AD-like pathology through coordinated enhancement of BBB-mediated Aβ clearance and suppression of microglial inflammatory amplification, highlighting PCSK9 as a multifaceted therapeutic target and supporting a BBB-oriented strategy for AD intervention.