TREM2 triggers microglial density and age‐related neuronal loss

Abstract

The microglial triggering receptor expressed on myeloid cells 2 (TREM2) signals via the activatory membrane adaptor molecule TYROBP. Genetic variants or mutations of TREM2 or TYROBP have been linked to inflammatory neurodegenerative diseases associated with aging. The typical aging process goes along with microglial changes and mild neuronal loss, but the exact contribution of TREM2 is still unclear. Aged TREM2 knock‐out mice showed decreased age‐related neuronal loss in the substantia nigra and the hippocampus. Transcriptomic analysis of the brains of 24 months old TREM2 knock‐out mice revealed 211 differentially expressed genes mostly downregulated and associated with complement activation and oxidative stress response pathways. Consistently, 24 months old TREM2 knock‐out mice showed lower transcription of microglial ( Aif1 and Tmem119 ), oxidative stress markers ( Inos, Cyba, and Cybb ) and complement components ( C1qa, C1qb, C1qc, C3, C4b, Itgam, and Itgb2 ), decreased microglial numbers and expression of the microglial activation marker Cd68, as well as accumulation of oxidized lipids. Cultured microglia of TREM2 knock‐out mice showed reduced phagocytosis and oxidative burst. Thus, microglial TREM2 contributes to age‐related microglial changes, phagocytic oxidative burst, and loss of neurons with possible detrimental effects during physiological aging.

Microglial Homeostasis Requires Balanced CSF-1/CSF-2 Receptor Signaling

“…Relevant changes include overexpression of TREM2, an innate immune receptor expressed on microglia that promotes clearance of apoptotic neurons and myelin debris (Poliani et al, 2015). Recent work indicates that, following uptake of apoptotic neurons or neuronal debris, TREM2 increases the expression of oxidative stress markers and complement components and suppresses the homeostatic function of microglia (Linnartz-Gerlach et al, 2019;Krasemann et al, 2017). The molecular mechanism could involve suppression of mitophagy either directly (Ulland et al, 2017;Wang et al, 2019) or as an indirect consequence of overloading of the degradative pathway by the ingested myelin (Safaiyan et al, 2016).…”

Identification of TYROBP and C1QB as Two Novel Key Genes With Prognostic Value in Gastric Cancer by Network Analysis

“…Yamada et al (58) reported that high C1QB expression was significantly related to poor prognosis in renal cell carcinoma. On the other hand, Linnartz-Gerlach et al (59) found that C1qB was downregulated in the brain of triggering receptor expressed on myeloid cells-2 (TREM2) knock-out mice. Interestingly, TREM2 has been reported to transmit intracellular signals through the associated transmembrane adapter TYROBP (60).…”

Microglial homeostasis requires balanced CSF-1/CSF-2 receptor signaling

“…Relevant changes include the overexpression of TREM2, an innate immune receptor expressed on microglia that promotes the clearance of apoptotic neurons and myelin debris (Poliani et al, 2015). Recent work indicates that following the uptake of the apoptotic neurons or neuronal debris, TREM2 increases the expression of oxidative stress markers and complement components and suppresses the homeostatic function of microglia (Linnartz-Gerlach et al, 2019, Krasemann et al, 2017. The molecular mechanism could involve suppression of mitophagy either directly , Wang et al, 2019 or as an indirect consequence of overloading of the degradative pathway by the ingested myelin (Safaiyan et al, 2016).…”