Modulation of inflammation in transgenic models of Alzheimer’s disease

Journal of Neuroinflammation

Magdalena Sastre¹  Loukia Katsouri¹  Amy M Birch¹ 

[1] Division of Brain Sciences, Imperial College London, London W12 0NN, UK

关键词: Anti-inflammatory;    Transgenics;    Tau;    Amyloid;    Astrocytes;    Microglia;    Inflammation;   

Others  :  824863
DOI  :  10.1186/1742-2094-11-25

 received in 2013-11-26, accepted in 2014-01-21,  发布年份 2014

【 摘 要 】

Over the past decade the process of inflammation has been a focus of increasing interest in the Alzheimer’s disease (AD) field, not only for its potential role in neuronal degeneration but also as a promising therapeutic target. However, recent research in this field has provided divergent outcomes, largely due to the use of different models and different stages of the disease when the investigations have been carried out. It is now accepted that microglia, and possibly astrocytes, change their activation phenotype during ageing and the stage of the disease, and therefore these are important factors to have in mind to define the function of different inflammatory components as well as potential therapies. Modulating inflammation using animal models of AD has offered the possibility to investigate inflammatory components individually and manipulate inflammatory genes in amyloid precursor protein and tau transgenics independently. This has also offered some hints on the mechanisms by which these factors may affect AD pathology. In this review we examine the different transgenic approaches and treatments that have been reported to modulate inflammation using animal models of AD. These studies have provided evidence that enhancing inflammation is linked with increases in amyloid-beta (Aβ) generation, Aβ aggregation and tau phosphorylation. However, the alterations on tau phosphorylation can be independent of changes in Aβ levels by these inflammatory mediators.

【 授权许可】

   
2014 Birch et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Blasko I, Stampfer-Kountchev M, Robatscher P, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B: How chronic inflammation can affect the brain and support the development of Alzheimer’s disease in old age: the role of microglia and astrocytes. Aging Cell 2004, 3:169-176.
• [2]Sastre M, Klockgether T, Heneka MT: Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms. Int J Dev Neurosci 2006, 24:167-176.
• [3]Benzing WC, Wujek JR, Ward EK, Shaffer D, Ashe KH, Younkin SG, Brunden KR: Evidence for glial-mediated inflammation in aged APPSW transgenic mice. Neurobiol Aging 1999, 20:581-589.
• [4]Bornemann KD, Wiederhold KH, Pauli C, Ermini F, Stalder M, Schnell L, Sommer B, Jucker M, Staufenbiel M: Abeta-induced inflammatory processes in microglia cells of APP23 transgenic mice. Am J Pathol 2001, 158:63-73.
• [5]Abbas N, Bednar I, Mix E, Marie S, Paterson D, Ljungberg A, Morris C, Winblad B, Nordberg A, Zhu J: Up-regulation of the inflammatory cytokines IFN-γ and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APPSWE transgenic mice. J Neuroimmunol 2002, 126:50-57.
• [6]Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F: Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation 2005, 2:22. BioMed Central Full Text
• [7]Moechars D, Dewachter I, Lorent K, Reversé D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute CV, Checler F, Godaux E, Cordell B, Van Leuven F: Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 1999, 274:6483-6492.
• [8]Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM: Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003, 39:409-421.
• [9]Janelsins MC, Mastrangelo MA, Oddo S, LaFerla FM, Federoff HJ, Bowers WJ: Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer’s disease mice. J Neuroinflammation 2005, 2:23. BioMed Central Full Text
• [10]Bellucci A, Westwood AJ, Ingram E, Casamenti F, Goedert M, Spillantini MG: Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein. Am J Pathol 2004, 165:1643-1652.
• [11]Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM: Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007, 53:337-351.
• [12]Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ, Rakic P, Davtyan H, Agadjanyan MG, Kepe V, Barrio JR, Bannykh S, Szekely CA, Pechnick RN, Town T: A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J Neurosci 2013, 33:6245-6256.
• [13]Roberts JC, Friel SL, Roman S, Perren M, Harper A, Davis JB, Richardson JC, Virley D, Medhurst AD: Autoradiographical imaging of PPARgamma agonist effects on PBR/TSPO binding in TASTPM mice. Exp Neurol 2009, 216:459-470.
• [14]Rapic S, Backes H, Viel T, Kummer MP, Monfared P, Neumaier B, Vollmar S, Hoehn M, Van der Linden A, Heneka MT, Jacobs AH: Imaging microglial activation and glucose consumption in a mouse model of Alzheimer’s disease. Neurobiol Aging 2013, 34:351-354.
• [15]Holland JP, Liang SH, Rotstein BH, Collier TL, Stephenson NA, Greguric I, Vasdev N: Alternative approaches for PET radiotracer development in Alzheimer’s disease: imaging beyond plaque. J Labelled Comp Radiopharm 2013. In press
• [16]Maeda J, Zhang MR, Okauchi T, Ji B, Ono M, Hattori S, Kumata K, Iwata N, Saido TC, Trojanowski JQ, Lee VM, Staufenbiel M, Tomiyama T, Mori H, Fukumura T, Suhara T, Higuchi M: In vivo positron emission tomographic imaging of glial responses to amyloid-beta and tau pathologies in mouse models of Alzheimer’s disease and related disorders. J Neurosci 2011, 31:4720-4730.
• [17]Colton CA, Vitek MP, Wink DA, Xu Q, Cantillana V, Previti ML, Van Nostrand WE, Weinberg JB, Dawson H: NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2006, 103:12867-12872.
• [18]Kummer MP, Hermes M, Delekarte A, Hammerschmidt T, Kumar S, Terwel D, Walter J, Pape HC, Konig S, Roeber S, Jessen F, Klockgether T, Korte M, Heneka MT: Nitration of tyrosine 10 critically enhances amyloid beta aggregation and plaque formation. Neuron 2011, 71:833-844.
• [19]Vom Berg J, Prokop S, Miller KR, Obst J, Kalin RE, Lopategui-Cabezas I, Wegner A, Mair F, Schipke CG, Peters O, Winter Y, Becher B, Heppner FL: Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 2012, 18:1812-1819.
• [20]Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Ikezu T: Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol 2007, 170:680-692.
• [21]He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, Staufenbiel M, Li R, Shen Y: Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice. J Cell Biol 2007, 178:829-841.
• [22]Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Heneka MT: Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci 2003, 23:9796-9804.
• [23]Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E, Borghgraef P, Evert BO, Dumitrescu-Ozimek L, Thal DR, Landreth G, Walter J, Klockgether T, van Leuven F, Heneka MT: Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci USA 2006, 103:443-448.
• [24]Montgomery SL, Mastrangelo MA, Habib D, Narrow WC, Knowlden SA, Wright TW, Bowers WJ: Ablation of TNF-RI/RII expression in Alzheimer’s disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-alpha suppressive therapeutic strategies in the brain. Am J Pathol 2011, 179:2053-2070.
• [25]Giuliani F, Vernay A, Leuba G, Schenk F: Decreased behavioral impairments in an Alzheimer mice model by interfering with TNF-alpha metabolism. Brain Res Bull 2009, 80:302-308.
• [26]Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, LaFerla FM, Olschowka JA, O’Banion MK: Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J Neurosci 2013, 33:5053-5064.
• [27]Shaftel SS, Kyrkanides S, Olschowka JA, Miller JN, Johnson RE, O’Banion MK: Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest 2007, 117:1595-1604.
• [28]Matousek SB, Ghosh S, Shaftel SS, Kyrkanides S, Olschowka JA, O’Banion MK: Chronic IL-1beta-mediated neuroinflammation mitigates amyloid pathology in a mouse model of Alzheimer’s disease without inducing overt neurodegeneration. J Neuroim Pharmacol 2012, 7:156-164.
• [29]Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, Masliah E, Mucke L: TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 2001, 7:612-618.
• [30]Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, Lin C, Mucke L: Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer’s disease. Nature 1997, 389:603-606.
• [31]Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA: Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 2008, 14:681-687.
• [32]Kummer MP, Vogl T, Axt D, Griep A, Vieira-Saecker A, Jessen F, Gelpi E, Roth J, Heneka MT: Mrp14 deficiency ameliorates amyloid β burden by increasing microglial phagocytosis and modulation of amyloid precursor protein processing. J Neurosci 2012, 32:17824-17829.
• [33]Kummer MP, Hulsmann C, Hermes M, Axt D, Heneka MT: Nitric oxide decreases the enzymatic activity of insulin degrading enzyme in APP/PS1 mice. J Neuroim Pharmacol 2012, 7:165-172.
• [34]Wilcock DM, Lewis MR, Van Nostrand WE, Davis J, Previti ML, Gharkholonarehe N, Vitek MP, Colton CA: Progression of amyloid pathology to Alzheimer’s disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J Neurosci 2008, 28:1537-1545.
• [35]Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, Liu S, Hegde A, Yan SF, Stern A, Luddy JS, Lue LF, Walker DG, Roher A, Buttini M, Mucke L, Li W, Schmidt AM, Kindy M, Hyslop PA, Stern DM, Du Yan SS: RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J 2004, 23:4096-4105.
• [36]Mucke L, Yu GQ, McConlogue L, Rockenstein EM, Abraham CR, Masliah E: Astroglial expression of human alpha(1)-antichymotrypsin enhances alzheimer-like pathology in amyloid protein precursor transgenic mice. Am J Pathol 2000, 157:2003-2010.
• [37]Nilsson LN, Bales KR, DiCarlo G, Gordon MN, Morgan D, Paul SM, Potter H: Alpha-1-antichymotrypsin promotes beta-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer’s disease. J Neurosci 2001, 21:1444-1451.
• [38]Padmanabhan J, Levy M, Dickson DW, Potter H: Alpha1-antichymotrypsin, an inflammatory protein overexpressed in Alzheimer’s disease brain, induces tau phosphorylation in neurons. Brain 2006, 129:3020-3034.
• [39]Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT: NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013, 493:674-678.
• [40]Jaeger LB, Dohgu S, Sultana R, Lynch JL, Owen JB, Erickson MA, Shah GN, Price TO, Fleegal-Demotta MA, Butterfield DA, Banks WA: Lipopolysaccharide alters the blood–brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer’s disease. Brain Behav Immun 2009, 23:507-517.
• [41]Herber DL, Roth LM, Wilson D, Wilson N, Mason JE, Morgan D, Gordon MN: Time-dependent reduction in Abeta levels after intracranial LPS administration in APP transgenic mice. Exp Neurol 2004, 190:245-253.
• [42]Herber DL, Mercer M, Roth LM, Symmonds K, Maloney J, Wilson N, Freeman MJ, Morgan D, Gordon MN: Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice. J Neuroim Pharmacol 2007, 2:222-231.
• [43]Barrientos RM, Higgins EA, Sprunger DB, Watkins LR, Rudy JW, Maier SF: Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus. Behav Brain Res 2002, 134:291-298.
• [44]Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG, Johnson RW: Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 2008, 22:301-311.
• [45]Otth C, Concha II, Arendt T, Stieler J, Schliebs R, Gonzalez-Billault C, Maccioni RB: AbetaPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576. J Alzheimer dis 2002, 4:417-430.
• [46]Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B: Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 1997, 94:13287-13292.
• [47]Arnaud L, Robakis NK, Figueiredo-Pereira ME: It may take inflammation, phosphorylation and ubiquitination to ‘tangle’ in Alzheimer’s disease. Neurodegener Dis 2006, 3:313-319.
• [48]Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ, Quigg RJ, Masliah E: Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer’s mice. Proc Natl Acad Sci USA 2002, 99:10837-10842.
• [49]Britschgi M, Takeda-Uchimura Y, Rockenstein E, Johns H, Masliah E, Wyss-Coray T: Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice. J Neuroinflammation 2012, 9:220. BioMed Central Full Text
• [50]Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM: Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci 2005, 25:8843-8853.
• [51]Sy M, Kitazawa M, Medeiros R, Whitman L, Cheng D, Lane TE, Laferla FM: Inflammation induced by infection potentiates tau pathological features in transgenic mice. Am J Pathol 2011, 178:2811-2822.
• [52]Tran HT, LaFerla FM, Holtzman DM, Brody DL: Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-beta accumulation and independently accelerates the development of tau abnormalities. J Neurosci 2011, 31:9513-9525.
• [53]Mastrangelo MA, Sudol KL, Narrow WC, Bowers WJ: Interferon-{gamma} differentially affects Alzheimer’s disease pathologies and induces neurogenesis in triple transgenic-AD mice. Am J Pathol 2009, 175:2076-2088.
• [54]Montgomery SL, Narrow WC, Mastrangelo MA, Olschowka JA, O’Banion MK, Bowers WJ: Chronic neuron- and age-selective down-regulation of TNF receptor expression in triple-transgenic Alzheimer disease mice leads to significant modulation of amyloid- and Tau-related pathologies. Am J Pathol 2013, 182:2285-2297.
• [55]Grathwohl SA, Kalin RE, Bolmont T, Prokop S, Winkelmann G, Kaeser SA, Odenthal J, Radde R, Eldh T, Gandy S, Aguzzi A, Staufenbiel M, Mathews PM, Wolburg H, Heppner FL, Jucker M: Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia. Nat Neuroscience 2009, 12:1361-1363.
• [56]Perry VH, Teeling J: Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol 2013, 35:601-612.
• [57]Lee DC, Rizer J, Hunt JB, Selenica ML, Gordon MN, Morgan D: Review: experimental manipulations of microglia in mouse models of Alzheimer’s pathology: activation reduces amyloid but hastens tau pathology. Neuropathol Appl Neurobiol 2013, 39:69-85.
• [58]Prokop S, Miller KR, Heppner FL: Microglia actions in Alzheimer’s disease. Acta Neuropathol 2013, 126:461-477.
• [59]Liu Z, Condello C, Schain A, Harb R, Grutzendler J: CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis. J Neurosci 2010, 30:17091-17101.
• [60]Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, Lamb BT: CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. American J Pathol 2010, 177:2549-2562.
• [61]Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, Haass C, LaFerla FM, Kretzschmar H, Herms J: Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neuroscience 2010, 13:411-413.
• [62]Cho SH, Sun B, Zhou Y, Kauppinen TM, Halabisky B, Wes P, Ransohoff RM, Gan L: CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J Biol Chem 2011, 286:32713-32722.
• [63]Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM: Control of microglial neurotoxicity by the fractalkine receptor. Nat Neuroscience 2006, 9:917-924.
• [64]Frenkel D, Wilkinson K, Zhao L, Hickman SE, Means TK, Puckett L, Farfara D, Kingery ND, Weiner HL, El Khoury J: Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat Comm 2030, 2013:4.
• [65]Thanopoulou K, Fragkouli A, Stylianopoulou F, Georgopoulos S: Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc Natl Acad Sci USA 2010, 107:20816-20821.
• [66]Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT: Regulation of tau pathology by the microglial fractalkine receptor. Neuron 2010, 68:19-31.
• [67]El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD: Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 2007, 13:432-438.
• [68]Naert G, Rivest S: CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer’s disease. J Neurosci 2011, 31:6208-6220.
• [69]Xiang Z, Ho L, Yemul S, Zhao Z, Qing W, Pompl P, Kelley K, Dang A, Qing W, Teplow D, Pasinetti GM: Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer’s disease neuropathology. Gene Expr 2002, 10:271-278.
• [70]Wyss-Coray T, Mucke L: Inflammation in neurodegenerative disease - a double-edged sword. Neuron 2002, 35:419-432.
• [71]Fonseca MI, Zhou J, Botto M, Tenner AJ: Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer’s disease. J Neurosci 2004, 24:6457-6465.
• [72]Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F, Mattson MP, Flavell RA, Mullan M: Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science 1999, 286:2352-2355.
• [73]Laporte V, Ait-Ghezala G, Volmar CH, Mullan M: CD40 deficiency mitigates Alzheimer’s disease pathology in transgenic mouse models. J Neuroinflammation 2006, 3:3. BioMed Central Full Text
• [74]Tan J, Town T, Crawford F, Mori T, DelleDonne A, Crescentini R, Obregon D, Flavell RA, Mullan MJ: Role of CD40 ligand in amyloidosis in transgenic Alzheimer’s mice. Nat Neurosci 2002, 5:1288-1293.
• [75]Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA: Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 2008, 28:6333-6341.
• [76]Reed-Geaghan EG, Reed QW, Cramer PE, Landreth GE: Deletion of CD14 attenuates Alzheimer’s disease pathology by influencing the brain’s inflammatory milieu. J Neurosci 2010, 30:15369-15373.
• [77]Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, Hooli B, Choi SH, Hyman BT, Tanzi RE: Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 2013, 78:631-643.
• [78]Park L, Wang G, Zhou P, Zhou J, Pitstick R, Previti ML, Younkin L, Younkin SG, Van Nostrand WE, Cho S, Anrather J, Carlson GA, Iadecola C: Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proc Natl Acad Sci USA 2011, 108:5063-5068.
• [79]Park L, Zhou J, Zhou P, Pistick R, El Jamal S, Younkin L, Pierce J, Arreguin A, Anrather J, Younkin SG, Carlson GA, McEwen BS, Iadecola C: Innate immunity receptor CD36 promotes cerebral amyloid angiopathy. Proc Natl Acad Sci USA 2013, 110:3089-3094.
• [80]Zhu Y, Hou H, Rezai-Zadeh K, Giunta B, Ruscin A, Gemma C, Jin J, Dragicevic N, Bradshaw P, Rasool S, Glabe CG, Ehrhart J, Bickford P, Mori T, Obregon D, Town T, Tan J: CD45 deficiency drives amyloid-beta peptide oligomers and neuronal loss in Alzheimer’s disease mice. J Neurosci 2011, 31:1355-1365.
• [81]Cameron B, Tse W, Lamb R, Li X, Lamb BT, Landreth GE: Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer’s disease. J Neurosci 2012, 32:15112-15123.
• [82]Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K: Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 2006, 129:3006-3019.
• [83]Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi K: Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 2008, 5:23. BioMed Central Full Text
• [84]Song M, Jin J, Lim JE, Kou J, Pattanayak A, Rehman JA, Kim HD, Tahara K, Lalonde R, Fukuchi K: TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflammation 2011, 8:92. BioMed Central Full Text
• [85]Lim JE, Kou J, Song M, Pattanayak A, Jin J, Lalonde R, Fukuchi K: MyD88 deficiency ameliorates beta-amyloidosis in an animal model of Alzheimer’s disease. Am J Pathol 2011, 179:1095-1103.
• [86]Michaud JP, Richard KL, Rivest S: MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer’s disease. Mol Neurodegener 2011, 6:5. BioMed Central Full Text
• [87]Richard KL, Filali M, Prefontaine P, Rivest S: Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1–42 and delay the cognitive decline in a mouse model of Alzheimer’s disease. J Neurosci 2008, 28:5784-5793.
• [88]Yamamoto M, Horiba M, Buescher JL, Huang D, Gendelman HE, Ransohoff RM, Ikezu T: Overexpression of monocyte chemotactic protein-1/CCL2 in β-amyloid precursor protein transgenic mice show accelerated diffuse β-amyloid deposition. Am J Pathol 2005, 166:1475-1485.
• [89]Kraft AW, Hu X, Yoon H, Yan P, Xiao Q, Wang Y, Gil SC, Brown J, Wilhelmsson U, Restivo JL, Cirrito JR, Holtzman DM, Kim J, Pekny M, Lee JM: Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J 2013, 27:187-198.
• [90]Akashi-Takamura S, Miyake K: Toll-like receptors (TLRs) and immune disorders. J Infect Chemother 2006, 12:233-240.
• [91]Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE: CD14 and Toll-like receptors 2 and 4 are required for fibrillar Aβ-stimulated microglial activation. J Neuroscience 2009, 29:11982-11992.
• [92]Solito E, Sastre M: Microglia function in Alzheimer’s disease. Front Pharmacol 2012, 3:14.
• [93]Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, Schjeide BM, Hooli B, Divito J, Ionita I, Jiang H, Laird N, Moscarillo T, Ohlsen KL, Elliott K, Wang X, Hu-Lince D, Ryder M, Murphy A, Wagner SL, Blacker D, Becker KD, Tanzi RE: Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am J Hum Genet 2008, 83:623-632.
• [94]Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, 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, Alzheimer Genetic Analysis Group: TREM2 variants in Alzheimer’s disease. N Engl J Med 2013, 368:117-127.
• [95]Hollingworth P, Sweet R, Sims R, Harold D, Russo G, Abraham R, Stretton A, Jones N, Gerrish A, Chapman J, Ivanov D, Moskvina V, Lovestone S, Priotsi P, Lupton M, Brayne C, Gill M, Lawlor B, Lynch A, Craig D, McGuinness B, Johnston J, Holmes C, Livingston G, Bass NJ, Gurling H, McQuillin A, Holmans P, Jones L, Devlin B, Klei L, Barmada MM, Demirci FY, DeKosky ST, Lopez OL, Passmore P, Owen MJ, O’Donovan MC, Mayeux R, Kamboh MI, Williams J, GERAD Consortium: Genome-wide association study of Alzheimer’s disease with psychotic symptoms. Mol Psychiatry 2012, 17:1316-1327.
• [96]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: Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 2013, 368:107-116.
• [97]Hawkes CA, McLaurin J: Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc Natl Acad Sci USA 2009, 106:1261-1266.
• [98]Majumdar A, Chung H, Dolios G, Wang R, Asamoah N, Lobel P, Maxfield FR: Degradation of fibrillar forms of Alzheimer’s amyloid beta-peptide by macrophages. Neurobiol Aging 2008, 29:707-715.
• [99]Malm TM, Koistinaho M, Parepalo M, Vatanen T, Ooka A, Karlsson S, Koistinaho J: Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol Dis 2005, 18:134-142.
• [100]Simard AR, Rivest S: Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. FASEB J 2004, 18:998-1000.
• [101]Streit WJ: Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosci 2006, 29:506-510.
• [102]Mildner A, Schlevogt B, Kierdorf K, Bottcher C, Erny D, Kummer MP, Quinn M, Bruck W, Bechmann I, Heneka MT, Priller J, Prinz M: Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J Neurosci 2011, 31:11159-11171.
• [103]Sieweke MH, Allen JE: Beyond stem cells: self-renewal of differentiated macrophages. Science 2013, 342:1242974.
• [104]Gomez-Nicola D, Fransen NL, Suzzi S, Perry VH: Regulation of microglial proliferation during chronic neurodegeneration. J Neurosci 2013, 33:2481-2493.
• [105]Varvel NH, Grathwohl SA, Baumann F, Liebig C, Bosch A, Brawek B, Thal DR, Charo IF, Heppner FL, Aguzzi A, Garaschuk O, Ransohoff RM, Jucker M: Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc Natl Acad Sci USA 2012, 109:18150-18155.
• [106]Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM: Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 2007, 10:1538-1543.
• [107]Browne TC, McQuillan K, McManus RM, O’Reilly JA, Mills KH, Lynch MA: IFN-gamma production by amyloid beta-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer’s disease. J Immunol 2013, 190:2241-2251.
• [108]Rogers J, Luber-Narod J, Styren SD, Civin WH: Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 1988, 9:339-349.
• [109]Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, Van Eldik LJ, Norris CM: Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci 2012, 32:16129-16140.
• [110]El Khoury J, Luster AD: Mechanisms of microglia accumulation in Alzheimer’s disease: therapeutic implications. Trends Pharmacol Sci 2008, 29:626-632.
• [111]Sastre M, Gentleman SM: NSAIDs: how they work and their prospects as therapeutics in Alzheimer’s disease. Front Aging Neurosci 2010, 2:20.
• [112]Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, Tran T, Ubeda O, Ashe KH, Frautschy SA, Cole GM: Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 2000, 20:5709-5714.
• [113]Lim GP, Yang F, Chu T, Gahtan E, Ubeda O, Beech W, Overmier JB, Hsiao-Ashec K, Frautschy SA, Cole GM: Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiol Aging 2001, 22:983-991.
• [114]Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE: NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 2003, 112:440-449.
• [115]Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, Kang DE, Marquez-Sterling N, Golde TE, Koo EH: A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001, 414:212-216.
• [116]Imbimbo BP, Giardino L, Sivilia S, Giuliani A, Gusciglio M, Pietrini V, Del Giudice E, D’Arrigo A, Leon A, Villetti G, Calza L: CHF5074, a novel gamma-secretase modulator, restores hippocampal neurogenesis potential and reverses contextual memory deficit in a transgenic mouse model of Alzheimer’s disease. J Alzheimer’s dis 2010, 20:159-173.
• [117]Imbimbo BP, Del Giudice E, Cenacchi V, Volta R, Villetti G, Facchinetti F, Riccardi B, Puccini P, Moretto N, Grassi F, Ottonello S, Leon A: In vitro and in vivo profiling of CHF5022 and CHF5074 Two beta-amyloid1-42 lowering agents. Pharmacol Res 2007, 55:318-328.
• [118]Balducci C, Mehdawy B, Mare L, Giuliani A, Lorenzini L, Sivilia S, Giardino L, Calza L, Lanzillotta A, Sarnico I, Pizzi M, Usiello A, Viscomi AR, Ottonello S, Villetti G, Imbimbo BP, Nisticò G, Forloni G, Nisticò R: The gamma-secretase modulator CHF5074 restores memory and hippocampal synaptic plasticity in plaque-free Tg2576 mice. J Alzheimer’s dis 2011, 24:799-816.
• [119]Sivilia S, Lorenzini L, Giuliani A, Gusciglio M, Fernandez M, Baldassarro VA, Mangano C, Ferraro L, Pietrini V, Baroc MF, Viscomi AR, Ottonello S, Villetti G, Imbimbo BP, Calzà L, Giardino L: Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice. BMC Neurosci 2013, 14:44. BioMed Central Full Text
• [120]Lleo A, Galea E, Sastre M: Molecular targets of non-steroidal anti-inflammatory drugs in neurodegenerative diseases. Cell Mol Life Sci 2007, 64:1403-1418.
• [121]Choi SH, Aid S, Caracciolo L, Minami SS, Niikura T, Matsuoka Y, Turner RS, Mattson MP, Bosetti F: Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer’s disease. J Neurochem 2013, 124:59-68.
• [122]Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, O’Banion K, Klockgether T, Van Leuven F, Landreth GE: Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 2005, 128:1442-1453.
• [123]Gomez-Isla T, Blesa R, Boada M, Clarimon J, Del Ser T, Domenech G, Ferro JM, Gomez-Anson B, Manubens JM, Martinez-Lage JM, Muñoz D, Peña-Casanova J, Torres F, TRIMCI Study Group: A randomized, double-blind, placebo controlled-trial of triflusal in mild cognitive impairment: the TRIMCI study. Alzheimer Dis Assoc Disord 2008, 22:21-29.
• [124]Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G: Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer’s disease. J Neurosci 2003, 23:7504-7509.
• [125]Dill J, Patel AR, Yang XL, Bachoo R, Powell CM, Li S: A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. J Neurosci 2010, 30:963-972.
• [126]Mandrekar-Colucci S, Karlo JC, Landreth GE: Mechanisms underlying the rapid peroxisome proliferator-activated receptor-gamma-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J Neurosci 2012, 32:10117-10128.
• [127]Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT: PPARgamma/RXRalpha-induced and CD36-mediated microglial amyloid-beta phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci 2012, 32:17321-17331.
• [128]Dumont M, Stack C, Elipenahli C, Jainuddin S, Gerges M, Starkova N, Calingasan NY, Yang L, Tampellini D, Starkov AA, Chan RB, Di Paolo G, Pujol A, Beal MF: Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice. Hum Mol Genet 2012, 21:5091-5105.
• [129]Searcy JL, Phelps JT, Pancani T, Kadish I, Popovic J, Anderson KL, Beckett TL, Murphy MP, Chen KC, Blalock EM, Landfield PW, Porter NM, Thibault O: Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer’s disease. J Alzheimers Dis 2012, 30:943-961.
• [130]Hanyu H, Sato T, Kiuchi A, Sakurai H, Iwamoto T: Pioglitazone improved cognition in a pilot study on patients with Alzheimer’s disease and mild cognitive impairment with diabetes mellitus. J Am Geriatr Soc 2009, 57:177-179.
• [131]Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD, Rosiglitazone in Alzheimer’s Disease Study G: Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease. Pharmacogenomics J 2006, 6:246-254.
• [132]Noble W, Garwood C, Stephenson J, Kinsey AM, Hanger DP, Anderton BH: Minocycline reduces the development of abnormal tau species in models of Alzheimer’s disease. FASEB J 2009, 23:739-750.
• [133]Familian A, Boshuizen RS, Eikelenboom P, Veerhuis R: Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation. Glia 2006, 53:233-240.
• [134]Ferretti MT, Bruno MA, Ducatenzeiler A, Klein WL, Cuello AC: Intracellular Abeta-oligomers and early inflammation in a model of Alzheimer’s disease. Neurobiol Aging 2012, 33:1329-1342.
• [135]Seabrook TJ, Jiang L, Maier M, Lemere CA: Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice. Glia 2006, 53:776-782.
• [136]Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Kim HS, Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim S, Suh YH: Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models. Neuropsychopharmacol 2007, 32:2393-2404.
• [137]Ryu JK, Franciosi S, Sattayaprasert P, Kim SU, McLarnon JG: Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus. Glia 2004, 48:85-90.
• [138]Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, Hirakawa A, Takeuchi H, Suzumura A, Ishiguro N, Kadomatsu K: Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis 2013, 4:e525.
• [139]Ruan L, Kang Z, Pei G, Le Y: Amyloid deposition and inflammation in APPswe/PS1dE9 mouse model of Alzheimer’s disease. Curr Alzheimer Res 2009, 6:531-540.
• [140]Shi JQ, Shen W, Chen J, Wang BR, Zhong LL, Zhu YW, Zhu HQ, Zhang QQ, Zhang YD, Xu J: Anti-TNF-alpha reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res 2011, 1368:239-247.
• [141]He P, Cheng X, Staufenbiel M, Li R, Shen Y: Long-term treatment of thalidomide ameliorates amyloid-like pathology through inhibition of beta-secretase in a mouse model of Alzheimer’s disease. PLoS One 2013, 8:e55091.
• [142]Tweedie D, Ferguson RA, Fishman K, Frankola KA, Van Praag H, Holloway HW, Luo W, Li Y, Caracciolo L, Russo I, Barlati S, Ray B, Lahiri DK, Bosetti F, Greig NH, Rosi S: Tumor necrosis factor-alpha synthesis inhibitor 3,6′-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer’s disease. J Neuroinflammation 2012, 9:106. BioMed Central Full Text