AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia

Poh, Luting; Fann, David Y.; Wong, Peiyan; Lim, Hong Meng; Foo, Sok Lin; Kang, Seok Woo; Rajeev, Vismitha; Selvaraji, Sharmelee; Vinaya, Rajagopal Iyer; Parathy, Nageiswari; Khan, Mohammad M.; Jo, Dong-Gyu; Drummond, Grant R; Sobey, Christopher G.; Lai, Mitchell K.P.; Chen, Christopher; Lim, Lina H.K.

doi:10.1101/2020.06.05.135228

Cited by 17 publications

(26 citation statements)

References 63 publications

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“…Increased expression and release of the inflammatory cytokine IL-6 are observed in HF patients (54). IL-6 promotes the infiltration and activation of mononuclear leukocytes (55) and activates the coagulation pathway and vascular endothelial cells, but inhibits myocardial function (56). In the present study, we found that M1 macrophage infiltration into the heart and the expression of IL-6 in the heart were elevated after BCAS, which may contribute to BCAS-induced cardiac dysfunction.…”

Section: Bcas Increases Cardiac Inflammationsupporting

confidence: 53%

Cardiac Dysfunction in a Mouse Vascular Dementia Model of Bilateral Common Carotid Artery Stenosis

Chopp

Zacharek

et al. 2021

Front. Cardiovasc. Med.

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Background: Cardiac function is associated with cognitive function. Previously, we found that stroke and traumatic brain injury evoke cardiac dysfunction in mice. In this study, we investigate whether bilateral common carotid artery stenosis (BCAS), a model that induces vascular dementia (VaD) in mice, induces cardiac dysfunction.Methods: Late-adult (6–8 months) C57BL/6J mice were subjected to sham surgery (n = 6) or BCAS (n = 8). BCAS was performed by applying microcoils (0.16 mm internal diameter) around both common carotid arteries. Cerebral blood flow and cognitive function tests were performed 21–28 days post-BCAS. Echocardiography was conducted in conscious mice 29 days after BCAS. Mice were sacrificed 30 days after BCAS. Heart tissues were isolated for immunohistochemical evaluation and real-time PCR assay.Results: Compared to sham mice, BCAS in mice significantly induced cerebral hypoperfusion and cognitive dysfunction, increased cardiac hypertrophy, as indicated by the increased heart weight and the ratio of heart weight/body weight, and induced cardiac dysfunction and left ventricular (LV) enlargement, indicated by a decreased LV ejection fraction (LVEF) and LV fractional shortening (LVFS), increased LV dimension (LVD), and increased LV mass. Cognitive deficits significantly correlated with cardiac deficits. BCAS mice also exhibited significantly increased cardiac fibrosis, increased oxidative stress, as indicated by 4-hydroxynonenal and NADPH oxidase-2, increased leukocyte and macrophage infiltration into the heart, and increased cardiac interleukin-6 and thrombin gene expression.Conclusions: BCAS in mice without primary cardiac disease provokes cardiac dysfunction, which, in part, may be mediated by increased inflammation and oxidative stress.

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Section: Bcas Increases Cardiac Inflammationsupporting

confidence: 53%

Cardiac Dysfunction in a Mouse Vascular Dementia Model of Bilateral Common Carotid Artery Stenosis

Chopp

Zacharek

et al. 2021

Front. Cardiovasc. Med.

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“…We recently demonstrated that 30 days of cerebral hypoperfusion due to BCAS results in hippocampal neuronal loss (45). In the present study it is noteworthy that,…”

Section: Discussionsupporting

confidence: 50%

“…We recently demonstrated that 30 days of cerebral hypoperfusion due to BCAS results in hippocampal neuronal loss (45). In the present study it is noteworthy that, compared with young sham mice, basal CBF was similarly reduced in old sham mice and in young mice subjected to cerebral hypoperfusion for 7 or 30 days.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal Transcriptome Profiling Reveals Common Disease Pathways in Chronic Hypoperfusion and Ageing

Baik

Selvaraji

Fann

et al. 2020

Preprint

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Vascular dementia (VaD) is a progressive cognitive impairment of vascular etiology. VaD is characterized by cerebral hypoperfusion, increased blood-brain barrier permeability and white matter lesions. An increased burden of VaD is expected due to rapidly aging populations. The hippocampus is particularly susceptible to hypoperfusion, and the resulting memory impairment may play a crucial role in VaD. Here we have investigated the hippocampal gene expression profile of young and old mice subjected to chronic cerebral hypoperfusion by bilateral common carotid artery stenosis (BCAS). Our data in sham-operated young and aged mice show the normal age-associated decline in cerebral blood flow and differential gene expression. BCAS and ageing caused broadly similar effects, however, BCAS-induced changes in hippocampal gene expression differed between young and aged mice. Specifically, transcriptomic analysis indicated that in comparison to young sham mice, many pathways altered by BCAS in young mice resembled those present in sham aged mice. Immunoblot analyses confirmed these findings. Finally, relative to young sham mice the cell type-specific profile of genes in both young BCAS and old sham animals further revealed common cell-specific genes. Our data provide a genetic-based molecular framework for chronic hypoperfusion-induced hippocampal damage and reveal common cellular signaling pathways likely to be important in the pathophysiology of VaD.

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“…In addition, AIM2 regulates the viability and apoptosis of human colorectal cancer cells via the PI3K/AKT signaling pathway (31). It has been demonstrated that, in AIM2 knockout mice, the production of pro-inflammatory cytokines mediated by the inflammasome is reduced, and apoptosis and pyroptosis are attenuated (32). Furthermore, AIM2 inhibits the invasion and metastasis of kidney cancer cells by enhancing autophagy induction (33).…”

Section: Discussionmentioning

confidence: 99%

AIM2 inhibits the proliferation, invasion and migration, and promotes the apoptosis of osteosarcoma cells by inactivating the PI3K/AKT/mTOR signaling pathway

et al. 2021

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Osteosarcoma is a primary bone tumor that mainly occurs in children and adolescents. Absent in melanoma 2 (AIM2) has been demonstrated to be involved in regulating the occurrence and development of cancer, exerting oncogenic and pro-cancer effects; however, its role in osteosarcoma is poorly understood. The present study aimed to explore the function and molecular mechanism of AIM2 in the progression of osteosarcoma. In the present study, AIM2 expression was predicted using the Cancer Cell Line Encyclopedia database and examined in several osteosarcoma cell lines using reverse transcription-quantitative PCR and western blotting. Following AIM2 overexpression, cell proliferation and apoptosis were examined using Cell Counting Kit-8, colony formation and TUNEL staining assays. The expression levels of proteins related to apoptosis, epithelial-mesenchymal transition (EMT) and the PI3K/AKT/mTOR signaling pathway were determined by western blotting. Additionally, cell invasion and migration were assessed using Transwell and wound healing assays. After addition of the PI3K/AKT/mTOR signaling pathway inhibitor LY294002 or activator 740Y-P, cell function analysis was performed. The results demonstrated that AIM2 was expressed at low levels in osteosarcoma cell lines. AIM2 overexpression inhibited proliferation, invasion, migration and EMT, and promoted apoptosis in osteosarcoma cells. Furthermore, the levels of phosphorylated (p)-PI3K, p-AKT and p-mTOR were markedly downregulated following AIM2 overexpression. Furthermore, LY294002 treatment had the same effects as AIM2 upregulation on osteosarcoma cell proliferation, apoptosis, invasion, migration and EMT. By contrast, 740Y-P reversed the effects of AIM2 overexpression on the behavior of osteosarcoma cells. Overall, the findings of the present study demonstrated that AIM2 may inhibit the progression of osteosarcoma by inactivating the PI3K/AKT/mTOR signaling pathway, and suggested that AIM2 may be a promising marker for the treatment of osteosarcoma.

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AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia

Cited by 17 publications

References 63 publications

Cardiac Dysfunction in a Mouse Vascular Dementia Model of Bilateral Common Carotid Artery Stenosis

Cardiac Dysfunction in a Mouse Vascular Dementia Model of Bilateral Common Carotid Artery Stenosis

Hippocampal Transcriptome Profiling Reveals Common Disease Pathways in Chronic Hypoperfusion and Ageing

AIM2 inhibits the proliferation, invasion and migration, and promotes the apoptosis of osteosarcoma cells by inactivating the PI3K/AKT/mTOR signaling pathway

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