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

Luting Poh, David Y. Fann, Peiyan Wong, Hong Meng Lim, Sok Lin Foo, Sung Wook Kang, Vismitha Rajeev, Sharmelee Selvaraji, Vinaya Rajagopal Iyer, Nageiswari Parathy, Mohammad Badruzzaman Khan, David C. Hess, Dong Gyu Jo, Grant R. Drummond, Christopher G. Sobey, Mitchell K.P. Lai, Christopher Li Hsian Chen, Lina H.K. Lim, Thiruma V. Arumugam

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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