Deletion of the Inflammasome Sensor <b><i>Aim2</i></b> Mitigates Aβ Deposition and Microglial Activation but Increases Inflammatory Cytokine Expression in an Alzheimer Disease Mouse Model

Abstract

Objective: Inflammation is clearly associated with Alzheimer disease (AD). Knockout of Nlrp3, a gene encoding an inflammasome sensor, has been shown to ameliorate AD pathology in a mouse model. Because AIM2 is the most dominant inflammasome sensor expressed in mouse brains, here we investigate whether Aim2 deletion also influences the phenotype of a 5XFAD AD mouse model. Methods: Quantitative RT-PCR, immunostaining, immunoblotting, and behavioral analyses were applied to compare wild-type, Aim2-/-, 5XFAD, and Aim2-/-;5XFAD mice. Results: We found that Aim2 knockout mitigates Aβ deposition in the cerebral cortex and hippocampus of 5XFAD mice. The activation of microglial cells is also reduced in Aim2-/-;5XFAD brains compared with 5XFAD brains. However, Aim2 knockout does not improve memory and anxiety phenotypes of 5XFAD mice in an open field, cued Y-maze, or Barnes maze. Compared with 5XFAD mice, Il-1 expression levels are not reduced in Aim2-/-;5XFAD mice. Unexpectedly, Il-6 and Il-18 expression levels in 5XFAD brains were further increased when Aim2 was deleted. Thus, inflammatory cytokine expression in 5XFAD brains is upregulated by Aim2 deletion through an unknown mechanism. Conclusion: Although Aim2 knockout mitigates Aβ deposition and microglial activation, Aim2 deletion does not have a beneficial effect on the spatial memory or cytokine expression of 5XFAD mice. Our findings suggest that Aβ aggregation and microglial activation may not always be correlated with the expression of inflammatory cytokines or cognitive function of 5XFAD mice. Our study also implies that different inflammasomes likely perform distinct roles in different physiological and/or pathological events.

Inflammasomes in neuroinflammatory and neurodegenerative diseases

“…Although the focus has been on the role of NLRP3 in AD, the role of other inflammasomes has also been characterized in the context of AD. The AIM2 inflammasome was shown to increase Aβ deposition, microglia activation, and cytokine production, but does not affect behavior or memory in transgenic 5xFAD mice (Wu et al , ). NLRP1 knockdown in APP/PS1 mice was shown to result in significantly reduced neuronal pyroptosis and to rescue cognitive impairments (Tan et al , ).…”

Extracellular vesicle-mediated amyloid transfer to neural progenitor cells: implications for RAGE and HIV infection

“…For instance, AIM2 is the dominant inflammasome sensor in the mouse brain. Its deletion caused a decrease in Aβ deposition and microglial activation along with IL-6 and IL-18 increase [65]. In the serum of HIV patients with higher viral load, AIM2 gene expression increased along with NLRP3, ASC, IL-1β, and IL-18 [66].…”

The role of innate immunity in Alzheimer's disease

“…216 The AIM2 inflammasome, which is activated by double-stranded DNA, has also been implicated in AD. 204 Aim2-deficient 5xFAD AD mice have decreased Aβ plaque load; however, this is not sufficient to rescue memory deficits. Additionally, 5xFAD;Aim2 -/mice have increased inflammation mediated by preserved IL-1 expression and an increase in the expression of pro-inflammatory cytokines IL-6…”

“…and IL-18 in the brain. 204 This may suggest parallel inflammatory mechanisms to compensate for the loss of Aim2 in AD mouse models. Interestingly, our laboratory and others have shown the loss of Aim2 impacts neuronal morphology and negatively influences several behaviors such as anxiety and memory.…”

“…Recent studies suggest a detrimental role for inflammasomes in AD. [201][202][203][204] Inflammasomes are multimolecular complexes that form following receptor activation in response to various DAMPs, PAMPs, and NAMPs. 205 The formation of these complexes initiates a signaling cascade in which active caspase-1 promotes the cleavage of inflammatory pro-IL-1β and pro-IL-18 cytokines into their active forms and also incites cell death.…”