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Small-molecule PCSK9 inhibition enhances BBB amyloid-β clearance and suppresses microglial inflammation in Alzheimer’s disease models
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  • Published: 02 April 2026

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

  • Jie Miao1,2,
  • Jing Wang3,4,
  • Wenhu Zhou5,6 &
  • …
  • Junhong Guo1,2 

Scientific Reports , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Biochemistry
  • Diseases
  • Neuroscience

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.

Data availability

The original contributions presented in the study are included in the article and/or Supplementary Material. The raw data supporting the conclusions of this article will be made available by the corresponding author upon reasonable request.

References

  1. Alzheimer’s disease facts and figures. Alzheimers Dement 20, 3708–3821, (2024). https://doi.org/10.1002/alz.13809 (2024).

  2. Knopman, D. S. et al. Alzheimer disease.. Nat. Rev. Dis. Primers 7, 33. https://doi.org/10.1038/s41572-021-00269-y (2021).

    Google Scholar 

  3. Thakur, S., Dhapola, R., Sarma, P., Medhi, B. & Reddy, D. H. Neuroinflammation in Alzheimer’s disease: Current progress in molecular signaling and therapeutics.. Inflammation 46, 1–17. https://doi.org/10.1007/s10753-022-01721-1 (2023).

    Google Scholar 

  4. Mintun, M. A. et al. Donanemab in early Alzheimer’s disease.. N. Engl. J. Med. 384, 1691–1704. https://doi.org/10.1056/NEJMoa2100708 (2021).

    Google Scholar 

  5. Ajoolabady, A. et al. PCSK9 in metabolism and diseases. Metabolism 163, 156064. https://doi.org/10.1016/j.metabol.2024.156064 (2025).

    Google Scholar 

  6. Pelucchi, S. et al. Neuronal PCSK9 regulates cognitive performances via the modulation of ApoER2 synaptic localization.. Pharmacol. Res. 213, 107652. https://doi.org/10.1016/j.phrs.2025.107652 (2025).

    Google Scholar 

  7. Poirier, S. et al. Implication of the proprotein convertase NARC-1/PCSK9 in the development of the nervous system.. J. Neurochem. 98, 838–850. https://doi.org/10.1111/j.1471-4159.2006.03928.x (2006).

    Google Scholar 

  8. Picard, C. et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) in Alzheimer’s disease: A genetic and proteomic multi-cohort study.. PLoS One 14, e0220254. https://doi.org/10.1371/journal.pone.0220254 (2019).

    Google Scholar 

  9. Canuel, M. et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1).. PLoS One 8, e64145. https://doi.org/10.1371/journal.pone.0064145 (2013).

    Google Scholar 

  10. Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713–1722. https://doi.org/10.1056/NEJMoa1615664 (2017).

    Google Scholar 

  11. Leng, F. & Edison, P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?. Nature Reviews Neurology 17, 157–172. https://doi.org/10.1038/s41582-020-00435-y (2021).

    Google Scholar 

  12. Ding, Z. et al. PCSK9 regulates expression of scavenger receptors and ox-LDL uptake in macrophages. Cardiovasc. Res. 114, 1145–1153. https://doi.org/10.1093/cvr/cvy079 (2018).

    Google Scholar 

  13. Sundararaman, S. S., Döring, Y. & van der Vorst, E. P. C. PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology. Biomedicines https://doi.org/10.3390/biomedicines9070793 (2021).

    Google Scholar 

  14. Mazura, A. D. et al. PCSK9 acts as a key regulator of Aβ clearance across the blood-brain barrier. Cell. Mol. Life Sci. 79, 212. https://doi.org/10.1007/s00018-022-04237-x (2022).

    Google Scholar 

  15. Ahamad, S., Mathew, S., Khan, W. A. & Mohanan, K. Development of small-molecule PCSK9 inhibitors for the treatment of hypercholesterolemia. Drug Discov. Today 27, 1332–1349. https://doi.org/10.1016/j.drudis.2022.01.014 (2022).

    Google Scholar 

  16. Ahamad, S. & Bhat, S. A. Recent update on the development of PCSK9 inhibitors for hypercholesterolemia treatment. J. Med. Chem. 65, 15513–15539. https://doi.org/10.1021/acs.jmedchem.2c01290 (2022).

    Google Scholar 

  17. Xu, S., Luo, S., Zhu, Z. & Xu, J. Small molecules as inhibitors of PCSK9: Current status and future challenges. Eur. J. Med. Chem. 162, 212–233. https://doi.org/10.1016/j.ejmech.2018.11.011 (2019).

    Google Scholar 

  18. Jin, P. et al. PCSK9 inhibition mitigates vulnerable plaque formation induced by hyperhomocysteinemia through regulating lipid metabolism and inflammation. Biochem. Pharmacol. 239, 117031. https://doi.org/10.1016/j.bcp.2025.117031 (2025).

    Google Scholar 

  19. Paduraru, E. et al. Zebrafish as a Potential Model for Neurodegenerative Diseases: A Focus on Toxic Metals Implications. Int J Mol Sci https://doi.org/10.3390/ijms24043428 (2023).

    Google Scholar 

  20. Hayat, M., Khola, N. U. H. & Ahmed, T. A Systematic Review of Preclinical Studies Investigating the Effects of Pharmacological Agents on Learning and Memory in Prolonged Aluminum-Exposure-Induced Neurotoxicity. Brain Sciences https://doi.org/10.3390/brainsci15080849 (2025).

    Google Scholar 

  21. Sun, C. et al. Eucommia ulmoides olive male flower extracts ameliorate Alzheimer’s disease-like pathology in zebrafish via regulating autophagy, acetylcholinesterase, and the dopamine transporter. Front. Mol. Neurosci. 15, 901953. https://doi.org/10.3389/fnmol.2022.901953 (2022).

    Google Scholar 

  22. Uvarajan, D. et al. Neuroprotective effects of berberine chloride against the aluminium chloride-induced Alzheimer’s disease in zebra fish larvae. Mol. Biotechnol. https://doi.org/10.1007/s12033-025-01392-x (2025).

    Google Scholar 

  23. Butterfield, D. A. & Boyd-Kimball, D. Oxidative stress, amyloid-β peptide, and altered key molecular pathways in the pathogenesis and progression of Alzheimer’s disease. J. Alzheimers Dis. 62, 1345–1367. https://doi.org/10.3233/jad-170543 (2018).

    Google Scholar 

  24. Storck, S. E. et al. Endothelial LRP1 transports amyloid-β(1–42) across the blood-brain barrier. J. Clin. Invest. 126, 123–136. https://doi.org/10.1172/jci81108 (2016).

    Google Scholar 

  25. Chen, J. et al. Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport. Signal Transduct. Target. Ther. 10, 331. https://doi.org/10.1038/s41392-025-02426-1 (2025).

    Google Scholar 

  26. Sheedy, F. J. et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol. 14, 812–820. https://doi.org/10.1038/ni.2639 (2013).

    Google Scholar 

  27. Liu, Y. et al. Beta-amyloid activates NLRP3 inflammasome via TLR4 in mouse microglia. Neurosci. Lett. 736, 135279. https://doi.org/10.1016/j.neulet.2020.135279 (2020).

    Google Scholar 

  28. Qi, Z. et al. PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36. Circulation 143, 45–61. https://doi.org/10.1161/circulationaha.120.046290 (2021).

    Google Scholar 

  29. Tang, Z. H. et al. New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway. Atherosclerosis 262, 113–122. https://doi.org/10.1016/j.atherosclerosis.2017.04.023 (2017).

    Google Scholar 

  30. Jaén, R. I. et al. Functional Crosstalk between PCSK9 Internalization and Pro-Inflammatory Activation in Human Macrophages: Role of Reactive Oxygen Species Release. Int J Mol Sci https://doi.org/10.3390/ijms23169114 (2022).

    Google Scholar 

  31. Mawuenyega, K. G. et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 3301774. https://doi.org/10.1126/science.1197623 (2010).

    Google Scholar 

  32. Courtemanche, H. et al. PCSK9 concentrations in cerebrospinal fluid are not specifically increased in Alzheimer’s disease. J. Alzheimers Dis. 62, 1519–1525. https://doi.org/10.3233/jad-170993 (2018).

    Google Scholar 

  33. Vilella, A. et al. PCSK9 ablation attenuates Aβ pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice. Brain Behav. Immun. 115, 517–534. https://doi.org/10.1016/j.bbi.2023.11.008 (2024).

    Google Scholar 

  34. Zheng, Y., Zhu, T., Li, G., Xu, L. & Zhang, Y. PCSK9 inhibitor protects against ischemic cerebral injury by attenuating inflammation via the GPNMB/CD44 pathway. Int. Immunopharmacol. 126, 111195. https://doi.org/10.1016/j.intimp.2023.111195 (2024).

    Google Scholar 

  35. Wagner, J. et al. PCSK9 inhibition attenuates alcohol-associated neuronal oxidative stress and cellular injury. Brain Behav. Immun. 119, 494–506. https://doi.org/10.1016/j.bbi.2024.04.022 (2024).

    Google Scholar 

  36. Su, T. & Si, Y. PCSK9 exacerbates sevoflurane-induced neuroinflammatory response and apoptosis by up-regulating cGAS-STING signal. Tissue Cell 93, 102739. https://doi.org/10.1016/j.tice.2025.102739 (2025).

    Google Scholar 

  37. Nadiga, A. P. R., Krishna, K. L. & Suman & A novel Zebrafish model of Alzheimer’s disease by Aluminium chloride; involving nitro-oxidative stress, neuroinflammation and cholinergic pathway. Eur. J. Pharmacol. 965, 176332. https://doi.org/10.1016/j.ejphar.2024.176332 (2024).

    Google Scholar 

  38. Hampel, H. et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 141, 1917–1933. https://doi.org/10.1093/brain/awy132 (2018).

    Google Scholar 

  39. Gence, L. et al. Gene expression patterns of the LDL receptor and its inhibitor Pcsk9 in the adult zebrafish brain suggest a possible role in neurogenesis. Eur. J. Neurosci. 61, e16586. https://doi.org/10.1111/ejn.16586 (2025).

    Google Scholar 

  40. Jaafar, A. K., Techer, R., Chemello, K., Lambert, G. & Bourane, S. PCSK9 and the nervous system: A no-brainer?. J. Lipid Res. 64, 100426. https://doi.org/10.1016/j.jlr.2023.100426 (2023).

    Google Scholar 

  41. Labusch, M., Mancini, L., Morizet, D. & Bally-Cuif, L. Conserved and divergent features of adult neurogenesis in zebrafish. Front. Cell Dev. Biol. 8, 525. https://doi.org/10.3389/fcell.2020.00525 (2020).

    Google Scholar 

  42. Gibbs, J. P. et al. Impact of target-mediated elimination on the dose and regimen of evolocumab, a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9). J. Clin. Pharmacol. 57, 616–626. https://doi.org/10.1002/jcph.840 (2017).

    Google Scholar 

  43. Giugliano, R. P. et al. Cognitive function in a randomized trial of evolocumab. N. Engl. J. Med. 377, 633–643. https://doi.org/10.1056/NEJMoa1701131 (2017).

    Google Scholar 

  44. Suswidiantoro, V. et al. The roles of PCSK9 in Alzheimer’s disease: A systematic review of clinical, genetic, and preclinical evidence. Life 15, 1851 (2025).

    Google Scholar 

  45. Tarasoff-Conway, J. M. et al. Clearance systems in the brain-implications for Alzheimer disease. Nat. Rev. Neurol. 11, 457–470. https://doi.org/10.1038/nrneurol.2015.119 (2015).

    Google Scholar 

  46. Adorni, M. P., Ruscica, M., Ferri, N., Bernini, F. & Zimetti, F. Proprotein convertase subtilisin/kexin type 9, brain cholesterol homeostasis and potential implication for Alzheimer’s disease. Front. Aging Neurosci. 11, 120. https://doi.org/10.3389/fnagi.2019.00120 (2019).

    Google Scholar 

  47. Livingston, G. et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396, 413–446. https://doi.org/10.1016/s0140-6736(20)30367-6 (2020).

    Google Scholar 

  48. Hussain, M. K. et al. Phytomolecules as Alzheimer’s therapeutics: A comprehensive review. Eur. J. Med. Chem. 288, 117401. https://doi.org/10.1016/j.ejmech.2025.117401 (2025).

    Google Scholar 

  49. Kimmel, C. B., Ballard, W. W., Kimmel, S. R., Ullmann, B. & Schilling, T. F. Stages of embryonic development of the zebrafish. Dev. Dyn. 203, 253–310. https://doi.org/10.1002/aja.1002030302 (1995).

    Google Scholar 

  50. Wu, Y. et al. The Neuroprotective Effects of Cyanidin Derivatives on AlCl(3)-Induced Zebrafish Model of Alzheimer’s Disease. Molecules https://doi.org/10.3390/molecules30183686 (2025).

    Google Scholar 

  51. Eigenmann, D. E. et al. Comparative study of four immortalized human brain capillary endothelial cell lines, hCMEC/D3, hBMEC, TY10, and BB19, and optimization of culture conditions, for an in vitro blood-brain barrier model for drug permeability studies. Fluids Barriers CNS 10, 33. https://doi.org/10.1186/2045-8118-10-33 (2013).

    Google Scholar 

  52. Wang, W. et al. A microfluidic chip recapitulating the human neurovascular unit with a functional blood-brain barrier for modeling gut-brain interactions. Lab Chip 25, 6504–6516. https://doi.org/10.1039/d5lc00937e (2025).

    Google Scholar 

  53. P, X. et al. The role of LRP1 in Aβ efflux transport across the blood-brain barrier and cognitive dysfunction in diabetes mellitus. Neurochem. Int. 160, 105417. https://doi.org/10.1016/j.neuint.2022.105417 (2022).

    Google Scholar 

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Acknowledgements

We thank Prof. Zhenyan Song’s group at Hunan University of Chinese Medicine for guidance and assistance with zebrafish behavioral experiments.

Funding

This work was supported by National Natural Science Foundation of China (No. 32571692), Fundamental Research Program of Shanxi Province (Grant No. 202303021222348, 202303021221212), STI2030-Major Projects (2021ZD 0201801), and National Key Research and Development Program of China (2023YFC3605400).

Author information

Authors and Affiliations

  1. Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China

    Jie Miao & Junhong Guo

  2. The First Clinical Medical School of Shanxi Medical University, Taiyuan, 030001, Shanxi, China

    Jie Miao & Junhong Guo

  3. Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Jing Wang

  4. National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Jing Wang

  5. Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China

    Wenhu Zhou

  6. Hunan Key Laboratory of The Research and Development of Novel Pharmaceutical Preparations, School of Pharmaceutical Science, Changsha Medical University, Changsha, 410219, Hunan, China

    Wenhu Zhou

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  1. Jie Miao
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  2. Jing Wang
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  3. Wenhu Zhou
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Contributions

J.M., J.W. and W.H.Z. conceived the study. J.M. and J.W. designed the methodology and performed the formal analysis. J.M. wrote the main manuscript text. W.H.Z. and J.H.G. reviewed and edited the manuscript. J.H.G. and W.H.Z. supervised the project. J.H.G., W.H.Z. and J.M. acquired funding. All authors reviewed the manuscript.

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Correspondence to Wenhu Zhou or Junhong Guo.

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Miao, J., Wang, J., Zhou, W. et al. Small-molecule PCSK9 inhibition enhances BBB amyloid-β clearance and suppresses microglial inflammation in Alzheimer’s disease models. Sci Rep (2026). https://doi.org/10.1038/s41598-026-46671-y

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  • Received: 04 January 2026

  • Accepted: 26 March 2026

  • Published: 02 April 2026

  • DOI: https://doi.org/10.1038/s41598-026-46671-y

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