Microglial TREM2 Mitigates Inflammatory Responses and Neuronal Apoptosis in Angiotensin II-Induced Hypertension in Middle-Aged Mice.

Xiaotian Xu,Jiukuan Hao,Lin Du,Tieyu Tang,Zhaoxia Wang,Jianxiong Jiang,Ming Yang,Xuetao Fu,Yingge Wang

doi:10.3389/fnagi.2021.716917

Abstract

Growing evidence suggests that hypertension and aging are prominent risk factors for the development of late-onset Alzheimer’s disease (LOAD) by inducement of neuroinflammation. Recent study showed that neuroinflammation via activated microglia induces reactive astrocytes, termed A1 astrocytes, that highly upregulate numerous classical complement cascade genes that are destructive to neurons in neurodegeneration diseases. Moreover, triggering receptor expressed on myeloid cells 2 (TREM2) is considered as one of the strongest single-allele genetic risk factors and plays important roles in neuroinflammation for LOAD. However, the mechanisms of microglia in the regulation of A1 astrocytic activation are still not clear. We introduced angiotensin II-induced hypertension in middle-aged mice and found that hypertension-upregulated TREM2 expression and A1 astrocytic activation were involved in neuroinflammation in the animal models used in this study. The in vitro results revealed that overexpression of microglial TREM2 not only mitigated microglial inflammatory response but also had salutary effects on reverse A1 astrocytic activation and neuronal toxicity.

Highlights

Alzheimer’s disease is the most common cause of all types of dementia (Lane et al, 2018; Scheltens et al, 2021), and sporadic Alzheimer’s disease (AD) usually occurs after the of 65, and is named late-onset AD (LOAD) (Rabinovici, 2019)
In addition to Aβ deposition, we observed that hypertension induces neuronal death by neuro-inflammation, which is in line with previous evidence that proved ANG II-dependent microglial activation induces neuroinflammation acts via crosstalk between central renin-angiotensin system type 1 receptors (AT1R) and toll-like receptor 4 (TLR4) (Biancardi et al, 2016; Liu et al, 2016).We further investigated the roles of neuroinflammation in the mouse models of this study
To verify the findings, Neuro2A cell viability assays confirmed that the overexpression of triggering receptor expressed on myeloid cells 2 (TREM2) in BV2 cells could protect Neuro2A cells from the toxic effects of MCM and ACM (Figures 12A,B). This present study showed that angiotensin II-induced hypertension significantly exacerbated M1 microglial activation, amyloid deposition, and neuronal apoptosis in middle-aged mice

Summary

Introduction

Alzheimer’s disease is the most common cause of all types of dementia (Lane et al, 2018; Scheltens et al, 2021), and sporadic Alzheimer’s disease (AD) usually occurs after the of 65, and is named late-onset AD (LOAD) (Rabinovici, 2019). Growing evidence suggests that hypertension plays an important role in LOAD (Kruyer et al, 2015; Lüders and Schrader, 2015) by causing Aβ plaque deposits and cerebral amyloid angiopathy (CAA) (Tsukuda et al, 2009; Carnevale et al, 2012; Elias et al, 2012). The mechanisms of hypertension causing dementia are still not fully understood, it has been found that neuroinflammation plays a pivotal role in the incidence and progression of AD (Iadecola, 2014; McMaster et al, 2015; Bolos et al, 2017). The M1 activation of microglia occurs in response to Aβ and other inflammatory stimuli, which have detrimental impacts on neurons, through the release of pro-inflammatory factors and various toxic substances (Sarlus and Heneka, 2017; Hansen et al, 2018)

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Conclusion