Downregulation of TREM2 expression exacerbates neuroinflammatory responses through TLR4-mediated MAPK signaling pathway in a transgenic mouse model of Alzheimer’s disease

John Bosco Ruganzu,Xiaoqian Peng,Yingying He,Xiangyuan Wu,Quzhao Zheng,Bo Ding,Chengheng Lin,Hongsong Guo,Zikang Yang,Xiao Zhang,Weina Yang

doi:10.1016/j.molimm.2021.12.018

John Bosco Ruganzu, Xiaoqian Peng + Show 9 more

Open Access

https://doi.org/10.1016/j.molimm.2021.12.018

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Journal: Molecular immunology	Publication Date: Dec 24, 2021
Citations: 21	License type: cc-by

Affiliation: Xi'an Jiaotong University

Abstract

Activation of glial cells and neuroinflammation play an important role in the onset and development of Alzheimer’s disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor in the brain that is involved in regulating neuroinflammation. However, the precise effects of TREM2 on neuroinflammatory responses and its underlying molecular mechanisms in AD have not been studied in detail. Here, we employed a lentiviral-mediated strategy to downregulation of TREM2 expression on microglia in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and BV2 cells. Our results showed that downregulation of TREM2 significantly aggravated AD-related neuropathology including Aβ accumulation, peri-plaque microgliosis and astrocytosis, as well as neuronal and synapse-associated proteins loss, which was accompanied by a decline in cognitive ability. The further mechanistic study revealed that downregulation of TREM2 expression initiated neuroinflammatory responses through toll-like receptor 4 (TLR4)-mediated mitogen-activated protein kinase (MAPK) signaling pathway and subsequent stimulating the production of pro-inflammatory cytokines in vivo and in vitro. Moreover, blockade of p38, JNK, and ERK1/2 inhibited the release of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) induced by Aβ1–42 in TREM2-knocked down BV2 cells. Taken together, these findings indicated that TREM2 might be a potential therapeutic target for AD and other neuroinflammation-related diseases.

Highlights

Alzheimer’s disease (AD) is the most common age-dependent neurodegenerative disorder characterized by severe memory loss, unusual behavior, and a progressive decline in cognitive function
The mechanistic study revealed that downregulation of Triggering receptor expressed on myeloid cells 2 (TREM2) expression increases pro-inflammatory cytokines production via TLR4mediated mitogen-activated protein kinase (MAPK) signaling pathway in the brain of amyloid precursor protein (APP)/PS1 mice and BV2 cells
The current study indicated that TREM2 downregulation leads to more obvious microgliosis and astrogliosis in the brain of APP/PS1 mice, which are closely associated with neuroinflammation

Summary

Introduction

Alzheimer’s disease (AD) is the most common age-dependent neurodegenerative disorder characterized by severe memory loss, unusual behavior, and a progressive decline in cognitive function. The classical neuropathological hallmarks of AD include extracellular β-amyloid (Aβ)-associated plaques, intraneuronal tau-associated neurofibrillary tangles (NFTs), and loss of neurons and synapses. Microglia activation was found to be related to the interaction between Aβ with several receptors including toll-like receptor 4 (TLR4) in AD patients and animal models [5]. Microglia aggregate around Aβ plaques and produce various proinflammatory cytokines and inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), reactive oxygen species, and nitric oxide [3, 8]. Pro-inflammatory cytokines promote amyloid precursor protein (APP) production and the process of APP proteolytic cleavage to increase the production of Aβ, resulting in a vicious cycle in AD [9,10,11]

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