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

  • Sci Rep. 2026 Apr 2;16(1):15780. doi: 10.1038/s41598-026-46671-y.
Jie Miao  1  2 ,  Jing Wang  3  4 ,  Wenhu Zhou  5  6 ,  Junhong Guo  7  8
Affiliations
  • 1. Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
  • 2. The First Clinical Medical School of Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
  • 3. Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • 4. National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • 5. Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China. [email protected].
  • 6. Hunan Key Laboratory of The Research and Development of Novel Pharmaceutical Preparations, School of Pharmaceutical Science, Changsha Medical University, Changsha, 410219, Hunan, China. [email protected].
  • 7. Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China. [email protected].
  • 8. The First Clinical Medical School of Shanxi Medical University, Taiyuan, 030001, Shanxi, China. [email protected].
PMID: 41927877 DOI: 10.1038/s41598-026-46671-y
Abstract

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.

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