Deficiency of macrophage migration inhibitory factor attenuates tau hyperphosphorylation in mouse models of Alzheimer’s disease
Open accessAbstract
BACKGROUND: Pathological features of Alzheimer's disease (AD) include aggregation of amyloid beta (Aβ) and tau protein. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been implicated in the toxicity of aggregated Aβ. It remains unclear whether MIF affects hyperphosphorylation and aggregation of tau. METHODS: The effects of MIF deficiency in tau hyperphosphorylation were examined in Mif (-/-) mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ) and in APP/PS1 transgenic mice mated with Mif (-/-) mice. MIF expression and astrocyte activation were evaluated in ICV-STZ mice using immunofluorescence staining. Cultured primary astrocytes were treated with high glucose to mimic STZ function in vitro, and the condition medium (CM) was collected. The level of tau hyperphosphorylation in neurons treated with the astrocyte CM was determined using Western blotting. RESULTS: MIF deficiency attenuated tau hyperphosphorylation in mice. ICV injection of STZ increased astrocyte activation and MIF expression in the hippocampus. MIF deficiency attenuated astrocyte activation in ICV-STZ mice. CM from high glucose-treated WT astrocytes increased tau hyperphosphorylation in cultured primary neurons, an effect absent from Mif (-/-) astrocytes and WT astrocytes treated with the MIF inhibitor ISO-1. ISO-1 had no direct effect on tau phosphorylation in cultured primary neurons. CONCLUSIONS: These results suggest that MIF deficiency is associated with reduced astrocyte activation and tau hyperphosphorylation in the mouse AD models tested. Inhibition of MIF and MIF-induced astrocyte activation may be useful in AD prevention and therapy.
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Other inflammatory factors such as IL-3, IL-6, IL-18, TNFα, and MIF are involved in tau phosphorylation and/or truncation.
“Other inflammatory factors such as IL-3, IL-6, IL-18, tumor necrosis factor-α (TNFα), and macrophage migration inhibitory factor (MIF) are also found to be involved in tau phosphorylation and/or truncation [166–170].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [166]
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- Authors
- Li, S.-Q., Yu, Y., Han, J.-Z., Wang, D., Liu, J., Qian, F., Fan, G.-H., Bucala, R., & Ye, R. D.
- Affiliations
- Shanghai Jiao Tong University (CN)
- GlaxoSmithKline (China) (CN)
- Yale University (US)
- Corresponding author
- Ye, Richard D.
- Venue
- Journal of Neuroinflammation
- Published
- 2015-09-17
- Volume
- 12
- Issue
- 1
- Pages
- 177-177
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC4574615
- OpenAlex
- W1942550365
- Cited by
- 59
- References
- 35
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 3 · 2017: 6 · 2016: 3
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (31270941, 81200843)
- National Basic Research Program of China (2012CB518001)
- the Specialized Research Fund for the Doctoral Program of Higher Education of China (20120073110069, 20120073120091)
- National Institutes of Health (R01 AI033503, R01 AI042310)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- macrophage migration inhibitory factor, tau hyperphosphorylation, Alzheimer's disease, astrocyte activation, streptozotocin, APP/PS1 mice, MIF knockout mice, high glucose, neuroinflammation, amyloid-beta, hippocampus
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Body Weight, Diabetes Mellitus, Experimental, Female, Glucose, Macrophage Migration-Inhibitory Factors, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Phosphorylation, Amyloid beta-Peptides, tau Proteins, Mice, Knockout, Mice, Primary Cell Culture
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