Insights into TREM2 biology by network analysis of human brain gene expression data

Abstract

Rare variants in TREM2 cause susceptibility to late-onset Alzheimer's disease. Here we use microarray-based expression data generated from 101 neuropathologically normal individuals and covering 10 brain regions, including the hippocampus, to understand TREM2 biology in human brain. Using network analysis, we detect a highly preserved TREM2-containing module in human brain, show that it relates to microglia, and demonstrate that TREM2 is a hub gene in 5 brain regions, including the hippocampus, suggesting that it can drive module function. Using enrichment analysis we show significant overrepresentation of genes implicated in the adaptive and innate immune system. Inspection of genes with the highest connectivity to TREM2 suggests that it plays a key role in mediating changes in the microglial cytoskeleton necessary not only for phagocytosis, but also migration. Most importantly, we show that the TREM2-containing module is significantly enriched for genes genetically implicated in Alzheimer's disease, multiple sclerosis, and motor neuron disease, implying that these diseases share common pathways centered on microglia and that among the genes identified are possible new disease-relevant genes.

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease

“…Quantification and analysis of PLD3 gene expression in brains was performed as previously described 35 . Briefly, the human data used here were provided by the UK Human Brain Expression Consortium 35 and consisted of 101 control post-mortem brains.…”

“…Briefly, the human data used here were provided by the UK Human Brain Expression Consortium 35 and consisted of 101 control post-mortem brains. All samples originated from individuals with no significant neurological history or neuropathological abnormality and were collected by the MRC Edinburgh Brain Bank 36 ensuring a consistent dissection protocol and sample handling procedure.…”

TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis

“…1A). Integrated network analysis suggested a central role for TREM2 in various brain areas (10), where it is mainly expressed in microglia cells regulating essential functions including phagocytosis and the removal of apoptotic neurons (11)(12)(13)(14).…”

Microglia provide unexplored avenues to attenuate cognitive decline following isoflurane exposure in susceptible young and elderly patients: A critical review of TREM2-DAP12 function and therapeutic potential

“…Initial phases involving endocytosis begin with regulation of Syk and then flow through PI3K-mediated pathways, including PLCg or PIP3-AKT routes. The secondary phase, maturation of the phagosome and phagosome-lysosome fusion events are mediated by Vav-Rac pathways after Syk interactions 53 . Figure 2 is an adapted and simplified pathway analysis of these two distinct routes of increased phagocytosis.…”