Deletion of interferon-regulatory factor-1 results in cognitive impairment

Abstract

Interferon-regulatory factor (IRF)-1-dependent genes in neurons play a role in ischemic neuronal death; however, the roles of IRF-1 in dementia are not well investigated. Therefore, we assessed the effect of IRF-1 on cognitive function using a vascular cognitive impairment mouse model created by chronic cerebral hypoperfusion. Male 10-week-old C57BL/6 (wild-type; WT) and IRF-1-knockout (IRF-1KO) mice were used in this study. A chronic cerebral hypoperfusion mouse model was generated by bilateral common carotid artery stenosis (BCAS) treatment. After 6 weeks of BCAS, the mice were subjected to the Morris water maze test five times a day for 5 days. In the Morris water maze task, escape latency was significantly prolonged in sham-operated IRF-1KO mice compared with sham-operated WT mice. However, BCAS treatment cancelled such difference in spatial learning between WT and IRF-1KO mice. BCAS treatment decreased CBF, but no significant difference was observed between the two strains after BCAS. Sham-operated IRF-1KO mice showed a decrease in mRNA expression of caspase-1 and an increase in IRF-2 expression in the hippocampus. Expression of angiotensin II type 2 (AT) receptor, which induces better cognitive function, is regulated by IRF-1; however, no obvious difference in AT receptor expression was observed between the two strains even after BCAS. These results suggest that IRF-1 has a protective effect on cognitive decline in a normal condition; however, there was no obvious effect on cognition after chronic cerebral hypoperfusion treatment.

Resveratrol reduces inflammatory response and detrimental effects in chronic cerebral hypoperfusion by down-regulating stimulator of interferon genes/TANK-binding kinase 1/interferon regulatory factor 3 signaling

“…The mammalian IRFs family includes transcription factors that induce type I IFNs (IRF3, IRF7), propagate type I IFN responses (IRF1, IRF4, and IRF5), and play a central role in innate immunity (Günthner and Anders, 2013). IRF-1 resists cognitive decline under normal conditions, but no obvious effect on cognition was observed in a bilateral common carotid artery stenosis mouse model (Mogi et al, 2018). The transcription factor IRF3 is constitutively expressed in all cell types and is essential for the induction of the IFN genes, IFN-α and IFN-β (Akira et al, 2006).…”

Mouse models of cerebral injury and cognitive impairment in hypertension

“…This pattern of damage has been demonstrated to be accompanied in a loss of cognitive function ( Nishio et al, 2010 ) with MRI imaging markers of damage similar to the one obtained in hypertensive patients ( Hall et al, 2022 ). Several studies demonstrated that also in this model the interplay between cerebral hypoperfusion, vascular damage and cognition is mediated by a neuroinflammation ( Mogi et al, 2018 ; Poh et al, 2021 ), adaptive ( Wang et al, 2022 ) and innate cerebral immunity ( Kakae et al, 2019 ). Finally, the alterations induced by this model in the brain glymphatic functions have been investigated to understand the potential mechanisms underlying the additional risk imposed by cerebrovascular factors in AD, proposing the reduced glymphatic drainage and reduced vascular pulsation may be key in the accumulation of β-amyloid amyloid in the brain ( Li et al, 2021 ).…”

A brief overview of a mouse model of cerebral hypoperfusion by bilateral carotid artery stenosis

“…Thus far, several behavioral tests have been used to assess the cognitive function of BCAS mice (Table 4). 13,14,[23][24][25]29,34,37,52,54,56,57,61,70,72,75,76,78,79,81,83,[98][99][100][101][102][103][104][105][106][107][108][109][110][111] For example, in the 8-arm radial maze test, which was used in the original study, spatial working memory declined in BCAS mice (2.5-month to 5-month-old) with 28 to 6 months of hypoperfusion duration. Reference memory was intact in 2.5 to 3-month-old mice with 1-month BCAS duration.…”