What happens to microglial TREM2 in Alzheimer's disease: Immunoregulatory turned into immunopathogenic?. (27th August 2015)

• Record Type: Journal Article
• Authors: Lue, L.-F.; Schmitz, C.; Walker, D.G.
• Is Part Of: Neuroscience. Volume 302(2015)
• Page Start: 138
• Page End: 150
• Publication Date: 2015-08-27
• Subjects: Aβ amyloid-beta -- AD Alzheimer's disease -- ADAM a disintegrin and metalloproteinase domain-containing protein -- CpG DNA cytosine-phosphate-guanidine deoxynucleic acid -- CSF cerebrospinal fluid -- CTF C-terminal fragment -- DAP12 DNAX-activating protein of 12 kDa -- EAE experimental autoimmune encephalomyelitis -- ERK extracellular signal-regulated kinase -- FTD frontotemporal dementia -- HSP60 heat shock protein 60 -- IFNγ interferon γ -- Ig immunoglobulin -- IL interleukin -- ITAM immunoreceptor tyrosine-based activation motif -- ITIM immunoreceptor tyrosine-based inhibitory motifs -- LAB Linker Activating B Cells -- LPS lipopolysaccharide -- ND non-demented controls -- NOS2 nitric oxide synthase 2 -- PI3K phosphorylation of phosphoinositide 3 kinase -- PLOSL Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy -- q-PCR quantitative polymerase chain reaction -- RIP regulated intramembrane proteolysis -- RT-PCR reverse transcription polymerase chain reaction -- sema semaphorins -- SHP1 Src homology 2-containing protein tyrosine phosphatase-1 -- shRNA short hairpin RNA -- sTREM2 soluble TREM2 -- Syk spleen tyrosine kinase -- TGN trans-Golgi network -- TLR Toll-like receptor -- TNFα tumor necrosis factor alpha -- TREM2 triggering receptor expressed on myeloid cells 2; phagocytic receptor -- microglia activation -- immunoregulation -- TREM2 mutation -- DAP12 immunoreceptor -- neurodegeneration; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2014.09.050
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Mutations in TREM2 gene increase the risk of several neurodegenerative diseases. As a phagocytic receptor, TREM2 also regulates inflammatory responses in microglia. Elevated expression of TREM2 is associated with Alzheimer's disease pathology. Current literature on non-mutated TREM2 in the brain and microglia are reviewed. Abnormal TREM2 functions could cause activated microglia to be immunopathogenic. Abstract: Microglia play major roles in initiation, coordination and execution of innate immunity in the brain. In the adult brain, these include maintenance of homeostasis, neuron and tissue repair, and eliminating infectious agents, apoptotic cells, and misfolded proteins. Some of these activities are accompanied by inflammatory reactions; and others are performed with no inflammatory effects. Under normal conditions, triggering receptor expressed on myeloid cells 2 (TREM2) belongs to the second category. It pairs with the adaptor protein DNAX-activating protein of 12 kDa (DAP12) to induce phagocytosis of apoptotic neurons without inflammatory responses, and to regulate Toll-like receptor-mediated inflammatory responses, and microglial activation. Although ligands for TREM2 are largely unknown, the mitochondrial heat shock protein 60, expressed on cell surface of apoptotic neurons, is a specific ligand that activates TREM2-mediated phagocytosis by microglia. TREM2 also phagocytoses amyloid beta peptide in cultured cells. Several TREM2 mutations have been identified recently that increase the risk of Alzheimer's disease, Frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis. Some of these mutations cause impaired proteolysis of full-length TREM2 at the plasma membrane to different degrees. The defects in the intramembrane cleavage result in dysfunction of phagocytosis signaling. The association of TREM2 mutations with neurodegenerative disease also calls for the understanding of the biology and pathological role of non-mutated TREM2 on human brains and microglia. This review provides a summary of current literature in TREM2 and DAP12 from several aspects, and proposes a theory that loss of TREM2 functions might contribute to the immunopathogenic role of microglia in Alzheimer's disease.