The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology
Author(s)
Fan, Qingyuan; Gayen, Manoshi; Singh, Neeraj; Gao, Fan; He, Wanxia; Hu, Xiangyou; Tsai, Li-Huei; Yan, Riqiang; ... Show more Show less
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The membrane-anchored CX3CL1 is best known to exert its signaling function through binding its receptor CX3CR1. This study demonstrates a novel function that CX3CL1 exerts. CX3CL1 is sequentially cleaved by α-, β-, and γ-secretase, and the released CX3CL1 intracellular domain (CX3CL1-ICD) would translocate into the cell nucleus to alter gene expression due to this back-signaling function. Amyloid deposition and neuronal loss were significantly reduced when membrane-anchored CX3CL1 C-terminal fragment (CX3CL1-ct) was overexpressed in Alzheimer's 5xFAD mouse model. The reversal of neuronal loss in 5xFAD can be attributed to increased neurogenesis by CX3CL1-ICD, as revealed by morphological and unbiased RNA-sequencing analyses. Mechanistically, this CX3CL1 back-signal likely enhances developmental and adult neurogenesis through the TGFβ2/3-Smad2/3 pathway and other genes important for neurogenesis. Induction of CX3CL1 back-signaling may not only be a promising novel mechanism to replenish neuronal loss but also for reducing amyloid deposition for Alzheimer's treatment.
Date issued
2019-06Department
Picower Institute for Learning and MemoryJournal
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
Qingyuan Fan et al. "The intracellular domain of CX3CL1 regulates adult neurogenesis and Alzheimer’s amyloid pathology." Journal of Experimental Medicine 216, 8 (June 2019): 1891–1903 © 2019 Fan et al
Version: Final published version
ISSN
0022-1007
1540-9538