Targeting phagocytosis for amyloid-β clearance: implications of morphology remodeling and microglia activation probed by bifunctional chimaeras
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.
Authors
- Yangmei Huang
- Binhua P. Zhou (ORCID: https://orcid.org/0000-0002-6136-6749)
- Jinyan Li (ORCID: https://orcid.org/0000-0003-1833-7413)
- Youqiao Wang (ORCID: https://orcid.org/0000-0003-0653-732X)
- Jiaojiao Zhao (ORCID: https://orcid.org/0009-0009-6870-7399)
- Xianzhang Bu
- Ziyi Liu (ORCID: https://orcid.org/0000-0003-1616-7537)
- Qiang Zhou (ORCID: https://orcid.org/0000-0001-7172-2500)
- Shuo Yang (ORCID: https://orcid.org/0000-0002-1534-8611)
- Xin Yue (ORCID: https://orcid.org/0000-0003-4202-3772)
- Yuxuan Zhao (ORCID: https://orcid.org/0009-0007-8747-7117)
- C. Y. Liao
- Y Zhang (ORCID: https://orcid.org/0000-0002-1144-4948)
- Weilin Zhou (ORCID: https://orcid.org/0009-0009-2615-6306)
- Zeyi Wang (ORCID: https://orcid.org/0009-0007-9340-3907)
Institutions
- Sun Yat-sen University (CN)
- Peking University (CN)
- Guizhou Minzu University (CN)
- First Affiliated Hospital of Jinan University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-30
- DOI
- https://doi.org/10.1038/s41467-025-63458-3
- Citations
- 2
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.33
Funders
- National Natural Science Foundation of China
- Shenzhen-Hong Kong Institute of Brain Science
- Basic and Applied Basic Research Foundation of Guangdong Province