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

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 () and Xianzhang Bu ()
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Youqiao Wang: Sun Yat-sen University
Zeyi Wang: Peking University Shenzhen Graduate School
Ziyi Liu: Sun Yat-sen University
Jinyan Li: Peking University Shenzhen Graduate School
Shuo Yang: Peking University Shenzhen Graduate School
Yuxuan Zhao: Sun Yat-sen University
Yangmei Huang: Peking University Shenzhen Graduate School
Chenyang Liao: Sun Yat-sen University
Yiqiu Zhang: Sun Yat-sen University
Jiaojiao Zhao: Sun Yat-sen University
Weilin Zhou: Sun Yat-sen University
Binhua Zhou: Guizhou Minzu University
Xin Yue: The First Affiliated Hospital of Jinan University
Qiang Zhou: Peking University Shenzhen Graduate School
Xianzhang Bu: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63458-3

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