Journal
JOURNAL OF NEUROINFLAMMATION
Volume 19, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12974-022-02679-5
Keywords
Alzheimer's disease; Amyloid-beta; Interleukin-3; Tau; Microglia; Astrocyte
Categories
Funding
- Science and Technology Innovation 2030 Major Projects
- National Natural Science Foundation of China
- Shanghai Municipal Science and Technology Major Project
- Research Start-up Fund of Huashan Hospital
- Excellence 2025 Talent Cultivation Program at Fudan University
- Taishan Scholars Program of Shandong Province
- ZHANGJIANG LAB, Tianqiao and Chrissy Chen Institute
- State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University, China
- [2022ZD0211600]
- [82071201]
- [81971032]
- [2018SHZDZX01]
- [2022QD002]
- [3030277001]
- [tsqn201812157]
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This study found that interleukin-3 (IL-3) secreted by astrocytes is associated with soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and mediates the correlation between A beta pathology and tau pathology in Alzheimer's disease (AD). IL-3 may play a crucial role in the spread from A beta pathology to tau pathology to cognitive impairment.
Background: Dysfunction of glial cell communication is involved in Alzheimer's disease (AD) pathogenesis, and the recent study reported that astrocytic secreted interleukin-3 (IL-3) participated in astrocyte-microglia crosstalk and restricted AD pathology in mice, but the effect of IL-3 on the pathological progression of AD in human is still unclear. Methods: A total of 311 participants with cerebrospinal fluid (CSF) IL-3, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and AD biomarkers were included from the Alzheimer's disease Neuroimaging Initiative (ADNI). We assessed the associations of IL-3 with sTREM2 and AD biomarkers at baseline, and with cognitive change in longitudinal study. The mediation models were used to explore the potential mechanism of how IL-3 affects AD pathology. Results: We found that CSF IL-3 was significantly associated with CSF sTREM2 and CSF AD core biomarkers (A beta 42, p-tau, and t-tau) at baseline, and was also markedly related to cognitive decline in longitudinal analysis. Moreover, mediation analysis revealed that CSF IL-3 modulated the level of CSF sTREM2 and contributed to tau pathology (as measured by CSF p-tau/t-tau) and subsequent cognitive decline. In addition, A beta pathology (as measured by CSF A beta 42) affected the development of tau pathology partly by modifying the levels of CSF IL-3 and CSF sTREM2. Furthermore, the effect of A beta pathology on cognitive decline was partially mediated by the pathway from CSF IL-3 and CSF sTREM2 to tau pathology. Conclusions: Our findings provide evidence to suggest that IL-3 is linked to sTREM2 and mediates the correlation between A beta pathology to tau pathology. It indicates that IL-3 may be a major factor in the spreading from A beta pathology to tau pathology to cognitive impairment.
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