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Dap12 microglia

Mari Tada, Takuya Konno, Masayoshi Tada, Toshiyuki Tezuka, Takeshi Miura, Naomi Mezaki, Ken-Ichi Okazaki, Musashi Arakawa, Kyoko Itoh, Toru Yamamoto, Hideaki Yokoo, Nobuaki Yoshikura, Kenji Ishihara, Masao Horie, Hirohide Takebayashi, Yasuko Toyoshima, Makoto Naito, Osamu Onodera, Masatoyo Nishizawa, Hitoshi Takahashi, Takeshi Ikeuchi, Akiyoshi Kakita
OBJECTIVE: To clarify the histopathological alterations of microglia in the brains of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) caused by mutations of the gene encoding the colony stimulating factor-1 receptor (CSF-1R). METHODS: We examined 5 autopsied brains and 1 biopsy specimen from a total of 6 patients with CSF-1R mutations. Detailed immunohistochemical, biochemical, and ultrastructural features of microglia were examined, and quantitative analyses were performed...
October 2016: Annals of Neurology
Peng Yuan, Carlo Condello, C Dirk Keene, Yaming Wang, Thomas D Bird, Steven M Paul, Wenjie Luo, Marco Colonna, David Baddeley, Jaime Grutzendler
Haplodeficiency of the microglia gene TREM2 increases risk for late-onset Alzheimer's disease (AD) but the mechanisms remain uncertain. To investigate this, we used high-resolution confocal and super-resolution (STORM) microscopy in AD-like mice and human AD tissue. We found that microglia processes, rich in TREM2, tightly surround early amyloid fibrils and plaques promoting their compaction and insulation. In Trem2- or DAP12-haplodeficient mice and in humans with R47H TREM2 mutations, microglia had a markedly reduced ability to envelop amyloid deposits...
May 18, 2016: Neuron
Jun-Ichi Satoh
Nasu-Hakola disease (NHD) is a rare intractable autosomal recessive disorder, characterized by pathological bone fractures and progressive dementia owing to multifocal bone cysts and leukoencephalopathy, caused by various genetic mutations of either DAP12 or TREM2. Loss-of-function of TREM2-DAP12, constituting a signaling complex on osteoclasts and microglia, plays a central role in the pathogenesis of NHD. Recently, NHD has been recognized as the disease entity designated "microgliopathy". However, at present, TREM2-specific ligands in microglia and the precise molecular mechanism underlying leukoencephalopathy remain to be investigated in order to establish an effective molecular targeted therapy for NHD...
May 2016: Brain and Nerve, Shinkei Kenkyū No Shinpo
Celeste M Karch, Lubov A Ezerskiy, Sarah Bertelsen, Alison M Goate
Late onset Alzheimer's disease (LOAD) is a genetically complex and clinically heterogeneous disease. Recent large-scale genome wide association studies (GWAS) have identified more than twenty loci that modify risk for AD. Despite the identification of these loci, little progress has been made in identifying the functional variants that explain the association with AD risk. Thus, we sought to determine whether the novel LOAD GWAS single nucleotide polymorphisms (SNPs) alter expression of LOAD GWAS genes and whether expression of these genes is altered in AD brains...
2016: PloS One
Zhonghui Guan, Julia A Kuhn, Xidao Wang, Bradley Colquitt, Carlos Solorzano, Smitha Vaman, Andrew K Guan, Zoe Evans-Reinsch, Joao Braz, Marshall Devor, Sherry L Abboud-Werner, Lewis L Lanier, Stavros Lomvardas, Allan I Basbaum
Although microglia have been implicated in nerve injury-induced neuropathic pain, the manner by which injured sensory neurons engage microglia remains unclear. We found that peripheral nerve injury induced de novo expression of colony-stimulating factor 1 (CSF1) in injured sensory neurons. CSF1 was transported to the spinal cord, where it targeted the microglial CSF1 receptor (CSF1R). Cre-mediated sensory neuron deletion of Csf1 completely prevented nerve injury-induced mechanical hypersensitivity and reduced microglial activation and proliferation...
January 2016: Nature Neuroscience
Junjie Xing, Amanda R Titus, Mary Beth Humphrey
Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a rare recessively inherited disease that is associated with early dementia and bone cysts with fractures. Here, we review the genetic causes of PLOSL with loss-of-function mutations or deletions in one of two genes, TYROBP and TREM2, encoding for two proteins DNAX-activating protein 12 (DAP12) and triggering receptor expressed on myeloid cells-2 (TREM2). TREM2 and DAP12 form an immunoreceptor signaling complex that mediates myeloid cell, including microglia and osteoclasts, development, activation, and function...
2015: Research and Reports in Biochemistry
Yuka Atagi, Chia-Chen Liu, Meghan M Painter, Xiao-Fen Chen, Christophe Verbeeck, Honghua Zheng, Xia Li, Rosa Rademakers, Silvia S Kang, Huaxi Xu, Steven Younkin, Pritam Das, John D Fryer, Guojun Bu
Several heterozygous missense mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to risk for a number of neurological disorders including Alzheimer disease (AD), Parkinson disease, and frontotemporal dementia. These discoveries have re-ignited interest in the role of neuroinflammation in the pathogenesis of neurodegenerative diseases. TREM2 is highly expressed in microglia, the resident immune cells of the central nervous system. Along with its adaptor protein, DAP12, TREM2 regulates inflammatory cytokine release and phagocytosis of apoptotic neurons...
October 23, 2015: Journal of Biological Chemistry
Meghan M Painter, Yuka Atagi, Chia-Chen Liu, Rosa Rademakers, Huaxi Xu, John D Fryer, Guojun Bu
Myeloid-lineage cells accomplish a myriad of homeostatic tasks including the recognition of pathogens, regulation of the inflammatory milieu, and mediation of tissue repair and regeneration. The innate immune receptor and its adaptor protein—triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12)—possess the ability to modulate critical cellular functions via crosstalk with diverse signaling pathways. As such, mutations in TREM2 and DAP12 have been found to be associated with a range of disease phenotypes...
2015: Molecular Neurodegeneration
Jun-ichi Satoh, Yoshihiro Kino, Nobutaka Motohashi, Tsuyoshi Ishida, Saburo Yagishita, Kenji Jinnai, Nobutaka Arai, Kiyotaka Nakamagoe, Akira Tamaoka, Yuko Saito, Kunimasa Arima
Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by formation of multifocal bone cysts and development of leukoencephalopathy, caused by genetic mutations of either DNAX-activation protein 12 (DAP12) or triggering receptor expressed on myeloid cells 2 (TREM2). Although increasing evidence suggests a defect in microglial TREM2/DAP12 function in NHD, the molecular mechanism underlying leukoencephalopathy with relevance to microglial dysfunction remains unknown. TREM2, by transmitting signals via the immunoreceptor tyrosine-based activation motif (ITAM) of DAP12, stimulates phagocytic activity of microglia, and ITAM signaling is counterbalanced by sialic acid-binding immunoglobulin (Ig)-like lectins (Siglecs)-mediated immunoreceptor tyrosine-based inhibitory motif (ITIM) signaling...
December 2015: Neuropathology: Official Journal of the Japanese Society of Neuropathology
Atsushi Sasaki, Akiyoshi Kakita, Kunihiro Yoshida, Takuya Konno, Takeshi Ikeuchi, Shintaro Hayashi, Hidenori Matsuo, Kei Shioda
Nasu-Hakola disease (NHD) is a form of presenile dementia associated with sclerosing leukoencephalopathy and polycystic lipomembranous osteodysplasia. This extremely rare inherited disease is caused by mutations in either DAP12 or TREM2. The present study was designed to assess the relationship between DAP12/TREM2 genotype, mRNA and protein expression levels by both Western blotting and immunohistochemistry, and the tissue distribution and pathomorphological phenotype of the microglia. Molecular genetic testing performed in three NHD cases confirmed that two cases had mutations in DAP12 and that one case carried a mutation in TREM2...
October 2015: Neurogenetics
Li Zhong, Xiao-Fen Chen, Zhen-Lian Zhang, Zhe Wang, Xin-Zhen Shi, Kai Xu, Yun-Wu Zhang, Huaxi Xu, Guojun Bu
Triggering receptor expressed on myeloid cells 2 (TREM2) is a DAP12-associated receptor expressed in microglia, macrophages, and other myeloid-derived cells. Previous studies have suggested that TREM2/DAP12 signaling pathway reduces inflammatory responses and promotes phagocytosis of apoptotic neurons. Recently, TREM2 has been identified as a risk gene for Alzheimer disease (AD). Here, we show that DAP12 stabilizes the C-terminal fragment of TREM2 (TREM2-CTF), a substrate for γ-secretase. Co-expression of DAP12 with TREM2 selectively increased the level of TREM2-CTF with little effects on that of full-length TREM2...
June 19, 2015: Journal of Biological Chemistry
Pietro Luigi Poliani, Yaming Wang, Elena Fontana, Michelle L Robinette, Yoshinori Yamanishi, Susan Gilfillan, Marco Colonna
Microglia contribute to development, homeostasis, and immunity of the CNS. Like other tissue-resident macrophage populations, microglia express the surface receptor triggering receptor expressed on myeloid cells 2 (TREM2), which binds polyanions, such as dextran sulphate and bacterial LPS, and activates downstream signaling cascades through the adapter DAP12. Individuals homozygous for inactivating mutations in TREM2 exhibit demyelination of subcortical white matter and a lethal early onset dementia known as Nasu-Hakola disease...
May 2015: Journal of Clinical Investigation
Masaaki Kobayashi, Hiroyuki Konishi, Toshiyuki Takai, Hiroshi Kiyama
Under pathological conditions, activated microglia play paradoxical roles and could have neurotoxic or neuroprotective effects. However, the signal determining how activated microglia affects the fate of neuronal cells remains largely unknown. Here we demonstrate that DNAX-activating protein of 12 kDa (DAP12), a transmembrane adaptor protein that contains an immunoreceptor tyrosine-based activation motif, is a critical regulator of microglial function after nerve injury. In a model of mouse hypoglossal nerve injury, the duration of microglial increase after nerve injury became shorter in mice lacking DAP12, although microglial morphology and total cell numbers were not significantly affected during early phase after nerve injury...
June 2015: Glia
Aditya Sunkaria, Supriya Bhardwaj, Avishek Halder, Aarti Yadav, Rajat Sandhir
Microglia play an important role in synaptic pruning and controlled phagocytosis of neuronal cells during developmental stages. However, the mechanisms that regulate these functions are not completely understood. The present study was designed to investigate the role of purinergic signalling in microglial migration and phagocytic activity during post-natal brain development. One-day-old BALB/c mice received lipopolysaccharide (LPS) and/or a purinergic analogue (2-methylthioladenosine-5'-diphosphate; 2MeSADP), intracerebroventrically (i...
March 2016: Molecular Neurobiology
L-F Lue, C Schmitz, D G Walker
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 12kDa (DAP12) to induce phagocytosis of apoptotic neurons without inflammatory responses, and to regulate Toll-like receptor-mediated inflammatory responses, and microglial activation...
August 27, 2015: Neuroscience
Paola Squarzoni, Guillaume Oller, Guillaume Hoeffel, Lorena Pont-Lezica, Philippe Rostaing, Donovan Low, Alain Bessis, Florent Ginhoux, Sonia Garel
Dysfunction of microglia, the tissue macrophages of the brain, has been associated with the etiology of several neuropsychiatric disorders. Consistently, microglia have been shown to regulate neurogenesis and synaptic maturation at perinatal and postnatal stages. However, microglia invade the brain during mid-embryogenesis and thus could play an earlier prenatal role. Here, we show that embryonic microglia, which display a transiently uneven distribution, regulate the wiring of forebrain circuits. Using multiple mouse models, including cell-depletion approaches and cx3cr1(-/-), CR3(-/-), and DAP12(-/-) mutants, we find that perturbing microglial activity affects the outgrowth of dopaminergic axons in the forebrain and the laminar positioning of subsets of neocortical interneurons...
September 11, 2014: Cell Reports
Teng Jiang, Lan Tan, Xi-Chen Zhu, Qiao-Quan Zhang, Lei Cao, Meng-Shan Tan, Li-Ze Gu, Hui-Fu Wang, Zheng-Zheng Ding, Ying-Dong Zhang, Jin-Tai Yu
Triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for Alzheimer's disease (AD), as its low-frequency variants increase the risk of this disease with an odds ratio similar to that of an APOE ɛ4 allele. To date, the expression and biologic functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was upregulated in microglia during disease progression. For the first time, we provided in vitro and in vivo evidence that this upregulation was attributed to the increased amyloid-β (Aβ)(1-42) levels in the brain...
December 2014: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Lorena Pont-Lezica, Wouter Beumer, Sabrina Colasse, Hemmo Drexhage, Marjan Versnel, Alain Bessis
Microglia colonise the brain parenchyma at early stages of development and accumulate in specific regions where they participate in cell death, angiogenesis, neurogenesis and synapse elimination. A recurring feature of embryonic microglial is their association with developing axon tracts, which, together with in vitro data, supports the idea of a physiological role for microglia in neurite development. Yet the demonstration of this role of microglia is lacking. Here, we have studied the consequences of microglial dysfunction on the formation of the corpus callosum, the largest commissure of the mammalian brain, which shows consistent microglial accumulation during development...
May 2014: European Journal of Neuroscience
Ukpong B Eyo, Long-Jun Wu
Unlike other resident neural cells that are of neuroectodermal origin, microglia are resident neural cells of mesodermal origin. Traditionally recognized for their immune functions during disease, new roles are being attributed to these cells in the development and maintenance of the central nervous system (CNS) including specific communication with neurons. In this review, we highlight some of the recent findings on the bidirectional interaction between neurons and microglia. We discuss these interactions along two lines...
2013: Neural Plasticity
Patrick Wunderlich, Konstantin Glebov, Nadja Kemmerling, Nguyen T Tien, Harald Neumann, Jochen Walter
Triggering receptor expressed on myeloid cells-2 (TREM2) and its signaling adaptor protein TYROBP/DAP12 play important roles in signal transduction in dendritic cells, osteoclasts, tissue macrophages, and microglia. Recently, TREM2 variants have been shown to be linked to late onset Alzheimer disease. Here, we demonstrate that TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis. The C-terminal fragment (CTF) of TREM2 generated by ectodomain shedding is cleaved by γ-secretase...
November 15, 2013: Journal of Biological Chemistry
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