Cited by 21Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Peripheral cancer attenuates amyloid pathology in Alzheimer’s disease via cystatin-c activation of TREM2

Li, Xinyan, Tang, Xiaomei, Zeng, Jinyu, Duan, Limin, Hou, Zhenye, Li, Lanfang, Guo, Yiqing, Chai, Changdong +8 more·2026·Cell

Abstract

Alzheimer's disease (AD) and cancer are among the most devastating diseases worldwide. Epidemiological data indicate that the incidence of AD significantly decreases in patients with a history of cancer. However, whether and how peripheral cancer may affect AD progression is yet to be studied. Here, we find that peripheral cancer inhibits amyloid pathology and rescues cognition via secretion of cystatin-c (Cyst-C), which binds amyloid oligomers and activates triggering receptor expressed on myeloid cells 2 (TREM2) in microglia, enabling microglia to degrade the pre-existing amyloid plaques in AD mice. These effects of Cyst-C are abolished by a cell-type-specific deletion (Cx3cr1TREM2-/-) or mutation of TREM2 (TREM2R47H) or Cyst-C (Cyst-CL68Q) in microglia. Together, these findings provide significant conceptual advances into cancer neuroscience and establish therapeutic avenues that are distinct from the present amyloid-lowering strategies, aiming at degrading the existing amyloid plaques for precision-targeted AD therapy.

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Crossref · 10.1016/j.cell.2025.12.020

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Authors
Li, X., Tang, X., Zeng, J., Duan, L., Hou, Z., Li, L., Guo, Y., Chai, C., Liu, J., Wang, Y., Zhu, L.-Q., Li, H., Zhang, T., Wang, Y., He, A., & Lu, Y.
Affiliations
  • Huazhong University of Science and Technology (CN)
  • Wuhan Union Hospital (CN)
  • Tongji Hospital (CN)
Corresponding author
Lu, Youming
Venue
Cell
Publisher
Elsevier BV
Published
2026-02
Volume
189
Issue
3
Pages
853-871.e31
ISSN
0092-8674 (ISSN-L)
OpenAlex
W7125416134
Cited by
21
References
96
Citations by year
2026: 21
FWCI
82.46
Type
journal article
Language
en
Open access
closed
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Huazhong University of Science and Technology
  • National Natural Science Foundation of China (32421003, 82430044, 82271486)
  • Ministry of Education of the People's Republic of China
  • Wuhan Union Hospital
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, cystatin C, TREM2, microglia, amyloid plaques, amyloid oligomers, amyloid clearance, CX3CR1, cancer neuroscience
MeSH terms
CX3C Chemokine Receptor 1, Alzheimer Disease, Amyloid, Animals, Disease Models, Animal, Humans, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Receptors, Immunologic, Amyloid beta-Peptides, Microglia, Mice, Cystatin C, Plaque, Amyloid

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