Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2

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• 作者：Jason D Ulrich ; Mary Beth Finn ; Yaming Wang ; Alice Shen…
• 关键词：Alzheimer’s disease ; TREM2 ; Microglia ; Amyloid β
• 刊名：Molecular Neurodegeneration
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：9
• 期：1
• 全文大小：749 KB
• 参考文献：1. Tanzi, RE The Genetics of Alzheimer Disease. In: Selkoe, DJ, Mandelkow, E, Holtzman, DM eds. (2011) The Biology of Alzheimer Disease. Cold Spring Harbor Press, New York, pp. 249-258
  2. Corder, EH, Saunders, AM, Strittmatter, WJ, Schmechel, DE, Gaskell, PC, Small, GW, Roses, AD, Haines, JL, Pericak-Vance, MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261: pp. 921-923 CrossRef
  3. Guerreiro, R, Wojtas, A, Bras, J, Carrasquillo, M, Rogaeva, E, Majounie, E, Cruchaga, C, Sassi, C, Kauwe, JSK, Younkin, S, Hazrati, L, Collinge, J, Pocock, J, Lashley, T, Williams, J, Lambert, JC, Amouyel, P, Goate, A, Rademakers, R, Morgan, K, Powell, J, St George-Hyslop, P, Singleton, A, Hardy, J (2013) TREM2 variants in Alzheimer’s disease. New Engl J Med 368: pp. 117-127 CrossRef
  4. Jonsson, T, Stefansson, H, Steinberg, S, Jonsdottir, I, Jonsson, PV, Snaedal, J, Bjornsson, S, Huttenlocher, J, Levey, AI, Lah, JJ, Rujescu, D, Hampel, H, Giegling, I, Andreassen, OA, Engedal, K, Ulstein, I, Djurovic, S, Ibrahim-Verbaas, C, Hofman, A, Ikram, MA, van Duijn, CM, Thorsteinsdottir, U, Kong, A, Stefansson, K (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. New Engl J Med 368: pp. 107-116 CrossRef
  5. Bouchon, A, Hernández-Munain, C, Cella, M, Colonna, M (2001) A Dap12-mediated pathway regulates expression of Cc chemokine receptor 7 and maturation of human dendritic cells. J Exp Med 194: pp. 1111-1122 m.194.8.1111" target="_blank" title="It opens in new window">CrossRef
  6. Paloneva, J, Manninen, T, Christman, G, Hovanes, K, Mandelin, J, Adolfsson, R, Bianchin, M, Bird, T, Miranda, R, Salmaggi, A, Tranebjaerg, L, Konttinen, Y, Peltonen, L (2002) Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 71: pp. 656-662 CrossRef
  7. Schmid, CD, Sautkulis, LN, Danielson, PE, Cooper, J, Hasel, KW, Hilbush, BS, Sutcliffe, JG, Carson, MJ (2002) Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem 83: pp. 1309-1320 CrossRef
  8. Takahashi, K, Rochford, CDP, Neumann, H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201: pp. 647-657 m.20041611" target="_blank" title="It opens in new window">CrossRef
  9. Piccio, L, Buonsanti, C, Mariani, M, Cella, M, Gilfillan, S, Cross, AH, Colonna, M, Panina-Bordignon, P (2007) Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur J Immunol 37: pp. 1290-1301 CrossRef
  10. Sieber, MW, Jaenisch, N, Brehm, M, Guenther, M, Linnartz-Gerlach, B, Neumann, H, Witte, OW, Frahm, C (2013) Attenuated inflammatory response in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice following stroke. PLoS One 8: pp. e52982 CrossRef
  11. Melchior, B, Garcia, AE, Hsiung, BK, Lo, KM, Doose, JM, Thrash, JC, Stalder, AK, Staufenbiel, M, Neumann, H, Carson, MJ (2010) Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer’s disease. ASN Neuro 2: pp. e00037 CrossRef
  12. Frank, S, Burbach, GJ, Bonin, M, Walter, M, Streit, W, Bechmann, I, Deller, T (2008) TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia 56: pp. 1438-1447 CrossRef
  13. Meyer-Luehmann, M, Spires-Jones, TL, Prada, C, Garcia-Alloza, M, de Calignon, A, Rozkalne, A, Koenigsknecht-Talboo, J, Holtzman, DM, Bacskai, BJ, Hyman, BT (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. N
• 刊物主题：Neurosciences; Neurology; Molecular Medicine;
• 出版者：BioMed Central
• ISSN：1750-1326

文摘

Background Recent genome-wide association studies linked variants in TREM2 to a strong increase in the odds of developing Alzheimer’s disease. The mechanism by which TREM2 influences the susceptibility to Alzheimer’s disease is currently unknown. TREM2 is expressed by microglia and is thought to regulate phagocytic and inflammatory microglial responses to brain pathology. Given that a single allele of variant TREM2, likely resulting in a loss of function, conferred an increased risk of developing Alzheimer’s disease, we tested whether loss of one functional trem2 allele would affect Aβ plaque deposition or the microglial response to Aβ pathology in APPPS1-21 mice. Results There was no significant difference in Aβ deposition in 3-month old or 7-month old APPPS1-21 mice expressing one or two copies of trem2. However, 3-month old mice with one copy of trem2 exhibited a marked decrease in the number and size of plaque-associated microglia. While there were no statistically significant differences in cytokine levels or markers of microglial activation in 3- or 7-month old animals, there were trends towards decreased expression of NOS2, C1qa, and IL1a in 3-month old TREM2+/?/sup> vs. TREM2+/+ mice. Conclusions Loss of a single copy of trem2 had no effect on Aβ pathology, but altered the morphological phenotype of plaque-associated microglia. These data suggest that TREM2 is important for the microglial response to Aβ deposition but that a 50% decrease inTREM2 expression does not affect Aβ plaque burden.