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Targeting phagocytosis for amyloid-β clearance: implications of morphology remodeling and microglia activation probed by bifunctional chimaeras

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  • Youqiao Wang

    (Sun Yat-sen University, School of Pharmaceutical Sciences)

  • Zeyi Wang

    (Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics)

  • Ziyi Liu

    (Sun Yat-sen University, School of Pharmaceutical Sciences)

  • Jinyan Li

    (Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics)

  • Shuo Yang

    (Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics)

  • Yuxuan Zhao

    (Sun Yat-sen University, School of Pharmaceutical Sciences)

  • Yangmei Huang

    (Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics)

  • Chenyang Liao

    (Sun Yat-sen University, School of Pharmaceutical Sciences)

  • Yiqiu Zhang

    (Sun Yat-sen University, School of Pharmaceutical Sciences)

  • Jiaojiao Zhao

    (Sun Yat-sen University, School of Pharmaceutical Sciences)

  • Weilin Zhou

    (Sun Yat-sen University, School of Pharmaceutical Sciences)

  • Binhua Zhou

    (Guizhou Minzu University, School of Ethnic Medicine)

  • Xin Yue

    (The First Affiliated Hospital of Jinan University)

  • Qiang Zhou

    (Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics)

  • Xianzhang Bu

    (Sun Yat-sen University, School of Pharmaceutical Sciences)

Abstract

Amyloid-β (Aβ), a key driver of Alzheimer’s disease (AD) pathogenesis, possesses diverse harmful and clearance-resistant structures that present substantial challenges to therapeutic development. Here, we demonstrate that modulating Aβ morphology, rather than Toll-like receptor 2 (TLR2)-dependent microglia activation, is essential for effective phagocytosis of Aβ species by microglia. By developing a bifunctional mechanistic probe (P2CSKn) designed to remodel Aβ and activate TLR2, we show it restructures soluble Aβ (sAβ) and fibrillar Aβ (fAβ) into less toxic hybrid aggregates (hPAβ). Critically, this structural remodeling protects microglia from Aβ toxicity while enabling robust phagocytosis. Moreover, although TLR2 activation mildly enhances Aβ uptake, it concurrently triggers detrimental inflammation that negates its benefits. Our findings establish morphological remodeling as the critical determinant of effective Aβ clearance and suggest a morphology-focused strategy for developing safe therapeutics for Aβ-related diseases.

Suggested Citation

  • Youqiao Wang & Zeyi Wang & Ziyi Liu & Jinyan Li & Shuo Yang & Yuxuan Zhao & Yangmei Huang & Chenyang Liao & Yiqiu Zhang & Jiaojiao Zhao & Weilin Zhou & Binhua Zhou & Xin Yue & Qiang Zhou & Xianzhang B, 2025. "Targeting phagocytosis for amyloid-β clearance: implications of morphology remodeling and microglia activation probed by bifunctional chimaeras," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63458-3
    DOI: 10.1038/s41467-025-63458-3
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    References listed on IDEAS

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    1. L. Palanikumar & Laura Karpauskaite & Mohamed Al-Sayegh & Ibrahim Chehade & Maheen Alam & Sarah Hassan & Debabrata Maity & Liaqat Ali & Mona Kalmouni & Yamanappa Hunashal & Jemil Ahmed & Tatiana Houho, 2021. "Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    2. Melanie Meyer-Luehmann & Tara L. Spires-Jones & Claudia Prada & Monica Garcia-Alloza & Alix de Calignon & Anete Rozkalne & Jessica Koenigsknecht-Talboo & David M. Holtzman & Brian J. Bacskai & Bradley, 2008. "Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease," Nature, Nature, vol. 451(7179), pages 720-724, February.
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