TREM2 deficiency aggravates α‐synuclein–induced neurodegeneration and neuroinflammation in Parkinson's disease models

Abstract

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) are known to increase the risk of developing Alzheimer disease and Parkinson's disease (PD). However, the potential role of TREM2 effect on synucleinopathy has not been characterized. In this study, we investigated whether loss of TREM2 function affects α‐synucleinopathy both in vitro and in vivo. In vitro, BV2 microglial cells were exposed to α‐synuclein (α‐syn) in the presence or absence of TREM2 small interference RNA. For in vivo studies, wild‐type controls and TREM2 gene knockout mice were intracranially injected in the substantia nigra with adeno‐associated viral vectors expressing human α‐syn (AAV‐SYN) to induce PD. Our results revealed that knockdown of TREM2 aggravated α‐syn‐induced inflammatory responses in BV2 cells and caused greater apoptosis in SH‐SY5Y cells treated with BV2‐conditioned medium. In mice, TREM2 knockout exacerbated dopaminergic neuron loss in response to AAV‐SYN. Moreover, both in vitro and in vivo TREM2 deficiency induced a shift from an anti‐inflammatory toward a proinflammatory activation status of microglia. These data suggest that impairing microglial TREM2 signaling aggravates proinflammatory responses to α‐syn and exacerbates α‐syn‐induced neurodegeneration by modulating microglial activation state.—Guo, Y., Wei, X., Yan, H., Qin, Y., Yan, S., Liu, J., Zhao, Y., Jiang, F., Lou, H. TREM2 deficiency aggravates α‐synuclein‐induced neurodegeneration and neuroinflammation in Parkinson's disease models. FASEB J. 33, 12164–12174 (2019). http://www.fasebj.org

Prebiotics Regulation of Intestinal Microbiota Attenuates Cognitive Dysfunction Induced by Surgery Stimulation in APP/PS1 Mice

“…It could relieve neuroinflammatory response and improve cognitive function in both neurodegenerative diseases and brain injury model [62,63]. The deficiency of TREM2 could affect the microglia function, aggravate the β amyloid and cause α-synuclein overexpression in neurodegenerative disease [63,64]. XOS intervention ameliorated the trends of microglia activation and TREM2 expression, indicating that TREM2-microglia signaling were related to intestinal dysbiosis after surgery.…”

“…TREM2 is a transmembrane receptor protein and expresses specifically by the microglia [61]. It could relieve neuroinflammatory response and improve cognitive function in both neurodegenerative diseases and brain injury model [62,63]. The deficiency of TREM2 could affect the microglia function, aggravate the β amyloid and cause α-synuclein overexpression in neurodegenerative disease [63,64].…”

Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

“…Central roles for phagocytic glia in neurodegeneration are becoming increasingly recognized as genome-wide association studies and transcriptomic analyses identify glial genes associated with increased risk or development of disease. For example, rare variants in TREM2 , a gene that encodes a microglial phagocytic receptor, are associated with increased risk of AD, FTD, and PD, and loss of TREM2 function exacerbates Aβ-, tau-, and α-synuclein-associated neurotoxicity (Griciuc et al; Guo et al, 2019; Leyns et al, 2019; Zhao et al, 2018). Reactive glia alter their morphology and gene expression profiles in response to diverse types of injury to promote neuronal survival by releasing trophic factors and clearing debris (Hammond et al, 2018).…”

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

“…The expression of TREM‐2 also impacts other neurodegenerative diseases. As an example, knockout of TREM‐2 causes α‐synuclein–induced neuronal loss in a model of PD (Guo et al ).…”