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https://www.readbyqxmd.com/read/27717139/vps35-dependent-recycling-of-trem2-regulates-microglial-function
#1
Jie Yin, Xiaocui Liu, Qing He, Lujun Zhou, Zengqiang Yuan, Siqi Zhao
Triggering receptor expressed on myeloid cells 2 (Trem2), an immune-modulatory receptor, is preferentially expressed in microglia of central nervous system. Trem2 might be involved in the development of Alzheimer's disease (AD) through regulating the inflammatory responses and phagocytosis of microglia. However, the intracellular trafficking of Trem2 remains unclear. In this study, we showed that Trem2 in the plasma membrane underwent endocytosis and recycling. Trem2 is internalized in a clathrin-dependent manner and then recycled back to the plasma membrane through vacuolar protein sorting 35 (Vps35), the key component of cargo recognition core of retromer complex, but not Rab11...
September 26, 2016: Traffic
https://www.readbyqxmd.com/read/27516385/the-human-specific-casp4-gene-product-contributes-to-alzheimer-related-synaptic-and-behavioural-deficits
#2
Yuji Kajiwara, Andrew McKenzie, Nate Dorr, Miguel A Gama Sosa, Gregory Elder, James Schmeidler, Dara L Dickstein, Ozlem Bozdagi, Bin Zhang, Joseph D Buxbaum
Recent studies have indicated that innate immune signalling molecules are involved in late-onset Alzheimer's disease (LOAD) risk. Amyloid beta (Aβ) accumulates in AD brain, and has been proposed to act as a trigger of innate immune responses. Caspase-4 is an important part of the innate immune response. We recently characterized transgenic mice carrying human CASP4, and observed that the mice manifested profound innate immune responses to lipopolysaccharide (LPS). Since these inflammatory processes are important in the aetiology of AD, we have now analysed the correlation of expression of caspase-4 in human brain with AD risk genes, and studied caspase-4 effects on AD-related phenotypes in APPswe/PS1deltaE9 (APP/PS1) mice...
August 11, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27356751/in-vitro-studies-implicate-an-imbalanced-activation-of-dendritic-cells-in-the-pathogenesis-of-murine-autoimmune-pancreatitis
#3
Luise Borufka, Erik Volmer, Sarah Müller, Robby Engelmann, Horst Nizze, Saleh Ibrahim, Robert Jaster
OBJECTIVES: MRL/MpJ mice spontaneously develop an autoimmune pancreatitis (AIP) and are widely used as a model to study the genetic, molecular and immunological basis of the disease. Here, we have addressed the question whether distinctive features of their dendritic cells (DCs) may predispose MRL/MpJ mice to the chronic inflammation. METHODS: Pancreatic lesions were analyzed employing histological methods. Cohorts of young (healthy) MRL/MpJ mice, adult (sick) individuals, and AIP-resistant CAST/EiJ mice were used to establish cultures of bone marrow (BM)-derived conventional DCs (cDCs)...
June 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27143430/opposing-roles-of-the-triggering-receptor-expressed-on-myeloid-cells-2-and-triggering-receptor-expressed-on-myeloid-cells-like-transcript-2-in-microglia-activation
#4
Honghua Zheng, Chia-Chen Liu, Yuka Atagi, Xiao-Fen Chen, Lin Jia, Longyu Yang, Wencan He, Xilin Zhang, Silvia S Kang, Terrone L Rosenberry, John D Fryer, Yun-Wu Zhang, Huaxi Xu, Guojun Bu
Mutations in triggering receptor expressed on myeloid cells 2 (TREM2), which has been proposed to regulate the inflammatory responses and the clearance of apoptotic neurons and/or amyloid-β, are genetically linked to increased risk for late-onset Alzheimer's disease (AD). Interestingly, a missense variant in TREM-like transcript 2 (TREML2), a structurally similar protein encoded by the same gene cluster with TREM2 on chromosome 6, has been shown to protect against AD. However, the molecular mechanisms by which TREM2 and TREML2 regulate the pathogenesis of AD, and their functional relationship, if any, remain unclear...
June 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/26202100/integrated-genomic-approaches-identify-major-pathways-and-upstream-regulators-in-late-onset-alzheimer-s-disease
#5
Xinzhong Li, Jintao Long, Taigang He, Robert Belshaw, James Scott
Previous studies have evaluated gene expression in Alzheimer's disease (AD) brains to identify mechanistic processes, but have been limited by the size of the datasets studied. Here we have implemented a novel meta-analysis approach to identify differentially expressed genes (DEGs) in published datasets comprising 450 late onset AD (LOAD) brains and 212 controls. We found 3124 DEGs, many of which were highly correlated with Braak stage and cerebral atrophy. Pathway Analysis revealed the most perturbed pathways to be (a) nitric oxide and reactive oxygen species in macrophages (NOROS), (b) NFkB and (c) mitochondrial dysfunction...
2015: Scientific Reports
https://www.readbyqxmd.com/read/26097896/microbiome-generated-amyloid-and-potential-impact-on-amyloidogenesis-in-alzheimer-s-disease-ad
#6
Yuhai Zhao, Walter J Lukiw
According to the 'amyloid cascade hypothesis of Alzheimer's disease' first proposed about 16 years ago, the accumulation of Aβ peptides in the human central nervous system (CNS) is the primary influence driving Alzheimer's disease (AD) pathogenesis, and Aβ peptide accretion is the result of an imbalance between Aβ peptide production and clearance. In the last 18 months multiple laboratories have reported two particularly important observations: (i) that because the microbes of the human microbiome naturally secrete large amounts of amyloid, lipopolysaccharides (LPS) and other related pro-inflammatory pathogenic signals, these may contribute to both the systemic and CNS amyloid burden in aging humans; and (ii) that the clearance of Aβ peptides appears to be intrinsically impaired by deficits in the microglial plasma-membrane enriched triggering receptor expressed in microglial/myeloid-2 cells (TREM2)...
July 2015: Journal of Nature and Science
https://www.readbyqxmd.com/read/25957402/dap12-stabilizes-the-c-terminal-fragment-of-the-triggering-receptor-expressed-on-myeloid-cells-2-trem2-and-protects-against-lps-induced-pro-inflammatory-response
#7
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
https://www.readbyqxmd.com/read/25893602/trem2-sustains-microglial-expansion-during-aging-and-response-to-demyelination
#8
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
https://www.readbyqxmd.com/read/23962980/a-physical-interaction-between-the-adaptor-proteins-dok3-and-dap12-is-required-to-inhibit-lipopolysaccharide-signaling-in-macrophages
#9
Qisheng Peng, Courtney L Long, Shikha Malhotra, Mary Beth Humphrey
DNAX-activating protein of 12 kD (DAP12) is an immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor protein found in myeloid cells and natural killer cells, and it couples to various receptors that mediate either cellular activation or inhibition. DAP12 inhibits Toll-like receptor (TLR) signaling, such as that of TLR4 in response to its ligand lipopolysaccharide (LPS), as well as cytokine responses by coupling to TREM2 (triggering receptor expressed on myeloid cells 2) at the plasma membrane...
August 20, 2013: Science Signaling
https://www.readbyqxmd.com/read/20640189/dual-induction-of-trem2-and-tolerance-related-transcript-tmem176b-in-amyloid-transgenic-mice-implications-for-vaccine-based-therapies-for-alzheimer-s-disease
#10
COMPARATIVE STUDY
Benoit Melchior, Angie E Garcia, Bor-Kai Hsiung, Katherine M Lo, Jonathan M Doose, J Cameron Thrash, Anna K Stalder, Matthias Staufenbiel, Harald Neumann, Monica J Carson
Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation...
July 12, 2010: ASN Neuro
https://www.readbyqxmd.com/read/19393017/differential-gene-expression-in-lps-ifngamma-activated-microglia-and-macrophages-in-vitro-versus-in-vivo
#11
COMPARATIVE STUDY
Christoph D Schmid, Benoit Melchior, Kokoechat Masek, Shweta S Puntambekar, Patria E Danielson, David D Lo, J Gregor Sutcliffe, Monica J Carson
Two different macrophage populations contribute to CNS neuroinflammation: CNS-resident microglia and CNS-infiltrating peripheral macrophages. Markers distinguishing these two populations in tissue sections have not been identified. Therefore, we compared gene expression between LPS (lipopolysaccharide)/interferon (IFN)gamma-treated microglia from neonatal mixed glial cultures and similarly treated peritoneal macrophages. Fifteen molecules were identified by quantative PCR (qPCR) as being enriched from 2-fold to 250-fold in cultured neonatal microglia when compared with peritoneal macrophages...
May 2009: Journal of Neurochemistry
https://www.readbyqxmd.com/read/17430113/pharmacological-targeting-of-ido-mediated-tolerance-for-treating-autoimmune-disease
#12
REVIEW
W Todd Penberthy
Cells at the maternal-fetal interface express indoleamine 2,3 dioxygenase (IDO) to consume all local tryptophan for the express purpose of starving adjacent maternal T cells of this most limiting and essential amino acid. This stops local T cell proliferation to ultimately result in the most dramatic example of immune tolerance, acceptance of the fetus. By contrast, inhibition of IDO using 1-methyl-tryptophan causes a sudden catastrophic rejection of the mammalian fetus. Immunomodulatory factors including IFNgamma, TNFalpha, IL-1, and LPS use IDO induction in responsive antigen presenting cells (APCs) also to transmit tolerogenic signals to T cells...
April 2007: Current Drug Metabolism
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