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Inhibition of caspase-1 ameliorates tauopathy and rescues cognitive impairment in SAMP8 mice

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Abstract

The inflammasome assembles leading to increased cleavage and activity of caspase-1 and downstream IL-1β release, which plays a significant role in the pathogenesis of Alzheimer’s disease (AD). Previous studies have shown that caspase-1-mediated neuroinflammation occurs early in AD process. However, the detailed role of caspase-1 in aging-related AD-like neuropathology is still unclear so far. In this study, by using SAMP8 mice, an animal model of accelerated aging, we detected the levels of caspase-1 in brains of 3-, 7-, and 11-month-old mice and observed that caspase-1 was activated during aging process. More importantly, we provided the evidence that VX-765, a selective inhibitor of caspase-1, significantly rescued spatial learning and memory impairments and reduced tau hyperphosphorylation in brains of SAMP8 mice at early stages of the disease. This amelioration might be attributed to IL-1β-induced hypoactivation of tau kinases. Our results imply that caspase-1 may represent as a potential therapeutic target for neurodegenerative tauopathies.

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Data are available from the corresponding authors.

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Funding

This work was supported by grants from the Taishan Scholars Program of Shandong Province (tsqn20161078), National Natural Science Foundation of China (81501103, 81771148), and Research Award Fund for Outstanding Young and Middle-aged Scientists of Shandong Province (BS2015SW006).

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Authors and Affiliations

  1. Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, 266071, People’s Republic of China

    Meng-Shan Tan, Yi Liu, Hao Hu, Chen-Chen Tan & Lan Tan

Authors
  1. Meng-Shan Tan
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  2. Yi Liu
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  3. Hao Hu
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  4. Chen-Chen Tan
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  5. Lan Tan
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Contributions

Conceptualization and study design: MST, LT. Experiment implementation: MST, YL, HH, CCT. Data collection and analysis: MST, YL, HH. Writing - original draft: MST, YL. Writing - review and editing: MST, HH, CCT, LT. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Meng-Shan Tan or Lan Tan.

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This study was conducted according to the recommendations in the guide for the care and use of laboratory animals of the National Institutes of Health and the approval of the committee on the Ethics of Animal Experiments of Qingdao Municipal Hospital.

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The authors have no conflict of interest to report.

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Tan, MS., Liu, Y., Hu, H. et al. Inhibition of caspase-1 ameliorates tauopathy and rescues cognitive impairment in SAMP8 mice. Metab Brain Dis 37, 1197–1205 (2022). https://doi.org/10.1007/s11011-022-00914-9

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