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Legumain Knockout Protects Against Aβ1–42-Induced AD-like Cognitive Deficits and Synaptic Plasticity Dysfunction Via Inhibiting Neuroinflammation Without Cleaving APP

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Abstract

Neuroinflammation is the important pathological feature of Alzheimer’s disease (AD). Legumain, a lysosomal cysteine protease, plays an important role in neuroinflammation during ischemic stroke and depressive disorder. Legumain is involved in AD process through cleaving APP; however, it is unclear if legumain can possibly modulate neuroinflammation without cleaving APP in AD. Thus, we established a mouse model of AD by single intracerebroventricular injections of Aβ1–42 in legumain knockout (KO) mice. The behavioral tests showed that legumain-KO effectively ameliorated cognitive impairment induced by Aβ1–42. Moreover, legumain deprivation significantly improves the synaptic plasticity damages in Aβ1–42-treated mice. Moreover, legumain-KO considerably inhibited the activation of microglia and reduced the expression of inflammatory cytokines in the hippocampus of Aβ1–42-treated mice. Interestingly, we found that legumain-KO inhibited TLR4/MyD88/NF-κB pathway, which was activated by Aβ1–42 in the hippocampus. In conclusion, our results suggested that legumain-KO reduced the level of neuroinflammation that was associated with inhibiting TLR4/MyD88/NF-κB pathways, thereby improving the hippocampal synaptic plasticity and reducing the cognitive impairments in Aβ1–42-treated mice.

Graphical abstract

Legumain knockout blocked microglia activation by inhibiting TLR4/MyD88/NF-κB signaling pathways, and further reduced inflammatory cytokine expression. As a result, legumain knockout alleviated synaptic damage and cognitive impairment induced by Aβ1–-42.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

We would like to acknowledge this work to our lab team Ph. D fellow Dr. Ekta kumara, who is a native English speaker, for her valuable comments and help.

Funding

This work was supported by grants from the National Natural Science Foundation of China (32070988).

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Authors and Affiliations

  1. College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin, 300071, People’s Republic of China

    Runwen Chen, Qiyue Zhang, Yuxing Yan, Yuying Zhang & Tao Zhang

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  1. Runwen Chen
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  2. Qiyue Zhang
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  3. Yuxing Yan
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  4. Yuying Zhang
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  5. Tao Zhang
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Contributions

Conceived and designed the experiment: Runwen Chen, Tao Zhang; performed the experiments: Runwen Chen, Qiyue Zhang, Yuxing Yan, Yuying Zhang; analyzed the data: Runwen Chen; wrote the manuscript: Runwen Chen, Yuying Zhang, Tao Zhang; and wrote revised version of manuscript: Runwen Chen, Tao Zhang.

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Correspondence to Tao Zhang.

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Chen, R., Zhang, Q., Yan, Y. et al. Legumain Knockout Protects Against Aβ1–42-Induced AD-like Cognitive Deficits and Synaptic Plasticity Dysfunction Via Inhibiting Neuroinflammation Without Cleaving APP. Mol Neurobiol 58, 1607–1620 (2021). https://doi.org/10.1007/s12035-020-02219-3

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