Targeting phagocytosis for amyloid-&#x3b2; 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; Xianzhang Bu

doi:10.1038/s41467-025-63458-3

PubMed · 40885741

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·Xianzhang Bu

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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.

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Microglia Amyloid beta-Peptides Phagocytosis Animals Toll-Like Receptor 2 Mice Alzheimer Disease Humans Mice, Inbred C57BL Journal Article

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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 Bu. 2025-08-30. Targeting phagocytosis for amyloid-β clearance: implications of morphology remodeling and microglia activation probed by bifunctional chimaeras.. https://doi.org/10.1038/s41467-025-63458-3

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