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AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia

Molecular Psychiatry volume 26, pages 4544–4560 (2021)Cite this article

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Abstract

Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response—particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1β and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial-cell activation, white-matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis, and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioral and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.

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Fig. 1: Effect of chronic cerebral hypoperfusion on inflammasome activation and cell death in the cerebral cortex and hippocampus over time following BCAS.
Fig. 2: Effect of chronic cerebral hypoperfusion on the levels of glial activation, white-matter integrity, and hippocampal neuronal density in the cerebral cortex and hippocampus following BCAS.
Fig. 3: Effect of chronic cerebral hypoperfusion on inflammasome-mediated programmed cell death in AIM2 KO mice following BCAS.
Fig. 4: Effect of chronic cerebral hypoperfusion on glial activation and myelin expression in the cerebral cortex and hippocampus of AIM2 KO mice following BCAS.
Fig. 5: Effect of chronic cerebral hypoperfusion on cortical white-matter integrity and hippocampal neuronal density in AIM2 KO mice following BCAS.
Fig. 6: Effect of chronic cerebral hypoperfusion on explorative locomotive behavior and spatial memory in AIM2 KO mice following BCAS.

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Acknowledgements

We thank Professor Jenny P. Ting (University of North Carolina, Chapel Hill, Chapel Hill, NC, USA) for providing the AIM2-deficient mice. Supplementary Figs. 1 and 9a in this article were created using BioRender.

Funding

This work was supported by the National Medical Research Council Research Grants (NMRC-CBRG-0102/2016 and NMRC/OFIRG/0036/2017), Singapore and the startup fund to TVA from La Trobe University, Melbourne, Australia.

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Authors and Affiliations

  1. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Luting Poh, David Y. Fann, Hong Meng Lim, Sok Lin Foo, Sung-Wook Kang, Vismitha Rajeev, Sharmelee Selvaraji, Lina H. K. Lim & Thiruma V. Arumugam

  2. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Luting Poh, Peiyan Wong, Vismitha Rajeev, Sharmelee Selvaraji, Vinaya Rajagopal Iyer, Nageiswari Parathy, Mitchell K. P. Lai & Christopher Li-Hsian Chen

  3. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    David Y. Fann

  4. Neuroscience and Behavioural Disorders Programme, Duke-NUS Medical School, Singapore, Singapore

    Peiyan Wong

  5. Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, USA

    Mohammad Badruzzaman Khan & David C. Hess

  6. School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea

    Dong-Gyu Jo & Thiruma V. Arumugam

  7. Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC, Australia

    Grant R. Drummond, Christopher G. Sobey & Thiruma V. Arumugam

  8. Memory, Aging and Cognition Centre, National University Health System, Singapore, Singapore

    Mitchell K. P. Lai & Christopher Li-Hsian Chen

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  1. Luting Poh
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Contributions

Study conception and design: T.V.A., L.P., and D.Y.F.; experiment or data collection: T.V.A., L.P., P.W., H.M.L., S.L.F., S-.W.K., V.R., S.S., D.Y.F., V.R.I., and N.P.; data analysis: L.P., P.W., V.R., S.S., D.Y.F., and T.V.A.; data interpretation: L.P., T.V.A., and D.Y.F; writing-manuscript preparation and intellectual input: T.V.A., L.P., D.Y.F., M.B.K., G.R.D., C.G.S., D.C.H., D-.G.J., M.K.P.L., C.L-.H.C., and L.H.K.L.; supervision and administration: T.V.A., D.Y.F., M.K.P.L., and C.L-.H.C.

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Correspondence to David Y. Fann or Thiruma V. Arumugam.

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Poh, L., Fann, D.Y., Wong, P. et al. AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia. Mol Psychiatry 26, 4544–4560 (2021). https://doi.org/10.1038/s41380-020-00971-5

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