Innate immunity in Alzheimer’s disease: the relevance of animal models?

Askew K, Li K, Olmos-Alonso A, Garcia-Moreno F, Liang Y, Richardson P, Tipton T, Chapman MA, Riecken K, Beccari S, Sierra A, Molnar Z, Cragg MS, Garaschuk O, Perry VH, Gomez-Nicola D (2017) Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep 18(2):391–405. doi:10.1016/j.celrep.2016.12.041 PubMedPubMedCentralCrossRef

Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM (2007) Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci 27(34):9115–9129. doi:10.1523/JNEUROSCI.2361-07.2007 PubMedCrossRefPubMedCentral

Baron R, Babcock AA, Nemirovsky A, Finsen B, Monsonego A (2014) Accelerated microglial pathology is associated with Abeta plaques in mouse models of Alzheimer’s disease. Aging Cell 13(4):584–595. doi:10.1111/acel.12210 PubMedPubMedCentralCrossRef

Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L, Millais SB, Donoghue S (2005) Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology 64(1):94–101PubMedCrossRef

Bellucci A, Westwood AJ, Ingram E, Casamenti F, Goedert M, Spillantini MG (2004) Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein. Am J Pathol 165(5):1643–1652. doi:10.1016/s0002-9440(10)63421-9 PubMedPubMedCentralCrossRef

Bilbo SD, Schwarz JM (2012) The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 33(3):267–286. doi:10.1016/j.yfrne.2012.08.006 PubMedPubMedCentralCrossRef

Biscaro B, Lindvall O, Tesco G, Ekdahl CT, Nitsch RM (2012) Inhibition of microglial activation protects hippocampal neurogenesis and improves cognitive deficits in a transgenic mouse model for Alzheimer’s disease. Neurodegener Dis 9(4):187–198. doi:10.1159/000330363 PubMedCrossRef

Biswas SK, Gangi L, Paul S, Schioppa T, Saccani A, Sironi M, Bottazzi B, Doni A, Vincenzo B, Pasqualini F, Vago L, Nebuloni M, Mantovani A, Sica A (2006) A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood 107(5):2112–2122. doi:10.1182/blood-2005-01-0428 PubMedCrossRef

Boche D, Perry VH, Nicoll JA (2013) Activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39(1):3–18. doi:10.1111/nan.12011 PubMedCrossRef

Boimel M, Grigoriadis N, Lourbopoulos A, Haber E, Abramsky O, Rosenmann H (2010) Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice. Exp Neurol 224(2):472–485. doi:10.1016/j.expneurol.2010.05.010 PubMedCrossRef

Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G (2007) PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6(2):137–143. doi:10.1016/j.cmet.2007.06.010 PubMedCrossRef

Boutajangout A, Quartermain D, Sigurdsson EM (2010) Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci 30(49):16559–16566. doi:10.1523/jneurosci.4363-10.2010 PubMedPubMedCentralCrossRef

Brendza RP, Bacskai BJ, Cirrito JR, Simmons KA, Skoch JM, Klunk WE, Mathis CA, Bales KR, Paul SM, Hyman BT, Holtzman DM (2005) Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic mice. J Clin Invest 115(2):428–433PubMedPubMedCentralCrossRef

Bruce-Keller AJ, Gupta S, Knight AG, Beckett TL, McMullen JM, Davis PR, Murphy MP, Van Eldik LJ, St Clair D, Keller JN (2011) Cognitive impairment in humanized APPxPS1 mice is linked to Abeta(1–42) and NOX activation. Neurobiol Dis 44(3):317–326. doi:10.1016/j.nbd.2011.07.012 PubMedPubMedCentralCrossRef

Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17(1):131–143. doi:10.1038/nn.3599 PubMedCrossRef

Buttini M, Masliah E, Barbour R, Grajeda H, Motter R, Johnson-Wood K, Khan K, Seubert P, Freedman S, Schenk D, Games D (2005) Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer’s disease. J Neurosci 25(40):9096–9101PubMedCrossRefPubMedCentral

Capani F, Ellisman MH, Martone ME (2001) Filamentous actin is concentrated in specific subpopulations of neuronal and glial structures in rat central nervous system. Brain Res 923(1–2):1–11PubMedCrossRef

Caruso D, Barron AM, Brown MA, Abbiati F, Carrero P, Pike CJ, Garcia-Segura LM, Melcangi RC (2013) Age-related changes in neuroactive steroid levels in 3xTg-AD mice. Neurobiol Aging 34(4):1080–1089. doi:10.1016/j.neurobiolaging.2012.10.007 PubMedCrossRef

CFAS (2001) Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study. Lancet 357(9251):169–175CrossRef

Chai X, Wu S, Murray TK, Kinley R, Cella CV, Sims H, Buckner N, Hanmer J, Davies P, O’Neill MJ, Hutton ML, Citron M (2011) Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J Biol Chem 286(39):34457–34467. doi:10.1074/jbc.M111.229633 PubMedPubMedCentralCrossRef

Chavant F, Deguil J, Pain S, Ingrand I, Milin S, Fauconneau B, Perault-Pochat MC, Lafay-Chebassier C (2010) Imipramine, in part through tumor necrosis factor alpha inhibition, prevents cognitive decline and beta-amyloid accumulation in a mouse model of Alzheimer’s disease. J Pharmacol Exp Ther 332(2):505–514. doi:10.1124/jpet.109.162164 PubMedCrossRef

Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP (2006) Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 3:27. doi:10.1186/1742-2094-3-27 PubMedPubMedCentralCrossRef

Colton CA, Wilcock DM, Wink DA, Davis J, Van Nostrand WE, Vitek MP (2008) The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP. J Alzheimers Dis 15(4):571–587PubMedPubMedCentralCrossRef

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(5123):921–923PubMedCrossRef

Corneveaux JJ, Myers AJ, Allen AN, Pruzin JJ, Ramirez M, Engel A, Nalls MA, Chen K, Lee W, Chewning K, Villa SE, Meechoovet HB, Gerber JD, Frost D, Benson HL, O’Reilly S, Chibnik LB, Shulman JM, Singleton AB, Craig DW, Van Keuren-Jensen KR, Dunckley T, Bennett DA, De Jager PL, Heward C, Hardy J, Reiman EM, Huentelman MJ (2010) Association of CR1, CLU and PICALM with Alzheimer’s disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum Mol Genet 19(16):3295–3301. doi:10.1093/hmg/ddq221 PubMedPubMedCentralCrossRef

Cosenza MA, Zhao ML, Si Q, Lee SC (2002) Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis. Brain Pathol 12(4):442–455PubMedCrossRef

Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ, Cotman CW (2012) Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J Neuroinflammation 9:179–197. doi:10.1186/1742-2094-9-179 PubMedPubMedCentralCrossRef

Davies DS, Ma J, Jegathees T, Goldsbury C (2016) Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer’s disease. Brain Pathol. doi:10.1111/bpa.12456 PubMedCrossRefPubMedCentral

Davis DG, Schmitt FA, Wekstein DR, Markesbery WR (1999) Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 58(4):376–388PubMedCrossRef

Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R, Alzheimer’s Disease Cooperative Study Steering Committee, Solanezumab Study Group (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4):311–321. doi:10.1056/NEJMoa1312889 PubMedCrossRef

Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, Hammers A, Tai YF, Fox N, Kennedy A, Rossor M, Brooks DJ (2008) Microglia, amyloid, and cognition in Alzheimer’s disease: an [¹¹C](R)PK11195-PET and [¹¹C]PIB-PET study. Neurobiol Dis 32(3):412–419PubMedCrossRef

Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I, Wall A, Ringheim A, Langstrom B, Nordberg A (2006) Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease. Brain 129(Pt 11):2856–2866. doi:10.1093/brain/awl178 PubMedCrossRef

Finckh U, Alberici A, Antoniazzi M, Benussi L, Fedi V, Giannini C, Gal A, Nitsch RM, Binetti G (2000) Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurology 54(10):2006–2008PubMedCrossRef

Frautschy SA, Yang F, Irrizarry M, Hyman B, Saido TC, Hsiao K, Cole GM (1998) Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 152(1):307–317PubMedPubMedCentral

Frommelt P, Schnabel R, Kuhne W, Nee LE, Polinsky RJ (1991) Familial Alzheimer disease: a large, multigeneration German kindred. Alzheimer Dis Assoc Disord 5(1):36–43PubMedCrossRef

Gallagher JJ, Minogue AM, Lynch MA (2013) Impaired performance of female APP/PS1 mice in the Morris water maze is coupled with increased Abeta accumulation and microglial activation. Neurodegener Dis 11(1):33–41. doi:10.1159/000337458 PubMedCrossRef

Gate D, Rezai-Zadeh K, Jodry D, Rentsendorj A, Town T (2010) Macrophages in Alzheimer’s disease: the blood-borne identity. J Neural Transm (Vienna, Austria: 1996) 117(8):961–970. doi:10.1007/s00702-010-0422-7 CrossRef

Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841–845. doi:10.1126/science.1194637 PubMedPubMedCentralCrossRef

Global Burden of Disease Study Collaborators (2015) Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386(9995):743–800. doi:10.1016/S0140-6736(15)60692-4 CrossRef

Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L et al (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349(6311):704–706PubMedCrossRef

Gordon MN, King DL, Diamond DM, Jantzen PT, Boyett KV, Hope CE, Hatcher JM, DiCarlo G, Gottschall WP, Morgan D, Arendash GW (2001) Correlation between cognitive deficits and Abeta deposits in transgenic APP+PS1 mice. Neurobiol Aging 22(3):377–385PubMedCrossRef

Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM (2001) Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol 49(6):697–705PubMedCrossRef

Griffin R, Nally R, Nolan Y, McCartney Y, Linden J, Lynch MA (2006) The age-related attenuation in long-term potentiation is associated with microglial activation. J Neurochem 99(4):1263–1272. doi:10.1111/j.1471-4159.2006.04165.x PubMedCrossRef

Guerreiro R, Wojtas A, Bras J, Carrasquillo MM, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin SG, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate AM, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton AB, Hardy J, Alzheimer Genetic Analysis Group (2012) TREM2 variants in Alzheimer’s disease. N Engl J Med 368(2):117–127PubMedPubMedCentralCrossRef

Gur RC, Turetsky BI, Matsui M, Yan M, Bilker W, Hughett P, Gur RE (1999) Sex differences in brain gray and white matter in healthy young adults: correlations with cognitive performance. J Neurosci 19(10):4065–4072PubMedCrossRefPubMedCentral

Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 42(9):781–785. doi:10.1038/ng.642 PubMedPubMedCentralCrossRef

Hanamsagar R, Bilbo SD (2016) Sex differences in neurodevelopmental and neurodegenerative disorders: focus on microglial function and neuroinflammation during development. J Steroid Biochem Mol Biol 160:127–133. doi:10.1016/j.jsbmb.2015.09.039 PubMedCrossRef

Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394. doi:10.1038/nn1997 PubMedCrossRef

Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185PubMedCrossRef

Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin SG, Holmans PA, O’Donovan M, Owen MJ, Williams J (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41(10):1088–1093PubMedPubMedCentralCrossRef

Harries LW, Hernandez D, Henley W, Wood AR, Holly AC, Bradley-Smith RM, Yaghootkar H, Dutta A, Murray A, Frayling TM, Guralnik JM, Bandinelli S, Singleton A, Ferrucci L, Melzer D (2011) Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell 10(5):868–878. doi:10.1111/j.1474-9726.2011.00726.x PubMedCrossRef

Hart AD, Wyttenbach A, Hugh Perry V, Teeling JL (2012) Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Brain Behav Immun 26(5):754–765. doi:10.1016/j.bbi.2011.11.006 PubMedPubMedCentralCrossRef

Hedges SB, Dudley J, Kumar S (2006) TimeTree: a public knowledge-base of divergence times among organisms. Bioinformatics 22(23):2971–2972. doi:10.1093/bioinformatics/btl505 PubMedCrossRef

Hefendehl JK, Wegenast-Braun BM, Liebig C, Eicke D, Milford D, Calhoun ME, Kohsaka S, Eichner M, Jucker M (2011) Long-term in vivo imaging of beta-amyloid plaque appearance and growth in a mouse model of cerebral beta-amyloidosis. J Neurosci 31(2):624–629. doi:10.1523/jneurosci.5147-10.2011 PubMedCrossRefPubMedCentral

Hefendehl JK, Neher JJ, Suhs RB, Kohsaka S, Skodras A, Jucker M (2014) Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell 13(1):60–69. doi:10.1111/acel.12149 PubMedCrossRef

Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28(33):8354–8360. doi:10.1523/JNEUROSCI.0616-08.2008 PubMedPubMedCentralCrossRef

Hjorth E, Zhu M, Toro VC, Vedin I, Palmblad J, Cederholm T, Freund-Levi Y, Faxen-Irving G, Wahlund LO, Basun H, Eriksdotter M, Schultzberg M (2013) Omega-3 fatty acids enhance phagocytosis of Alzheimer’s disease-related amyloid-beta42 by human microglia and decrease inflammatory markers. J Alzheimers Dis 35(4):697–713. doi:10.3233/jad-130131 PubMedCrossRef

Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C, O’Campo K, Hardy J, Prada CM, Eckman C, Younkin S, Hsiao K, Duff K (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4(1):97–100PubMedCrossRef

Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Ruther E, Schurmann B, Heun R, Kolsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Gallacher J, Hull M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alperovitch A, Lathrop M, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snaedal J, Bjornsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossu P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschneider M, Morgan K, Younkin SG, Owen MJ, O’Donovan M, Amouyel P, Williams J (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43(5):429–435. doi:10.1038/ng.803 PubMedPubMedCentralCrossRef

Holmes C (2013) Systemic inflammation and Alzheimer’s disease. Neuropathol Appl Neurobiol 39(1):51–68. doi:10.1111/j.1365-2990.2012.01307.x PubMedCrossRef

Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH (2003) Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 74(6):788–789PubMedPubMedCentralCrossRef

Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372(9634):216–223. doi:10.1016/S0140-6736(08)61075-2 PubMedCrossRef

Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73(10):768–774PubMedPubMedCentralCrossRef

Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274(5284):99–102PubMedCrossRef

Hu X, Pickering E, Liu YC, Hall S, Fournier H, Katz E, Dechairo B, John S, Van Eerdewegh P, Soares H (2011) Meta-analysis for genome-wide association study identifies multiple variants at the BIN1 locus associated with late-onset Alzheimer’s disease. PLoS One 6(2):e16616. doi:10.1371/journal.pone.0016616 PubMedPubMedCentralCrossRef

Janelsins MC, Mastrangelo MA, Oddo S, LaFerla FM, Federoff HJ, Bowers WJ (2005) 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 2:23PubMedPubMedCentralCrossRef

Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13(2):159–170. doi:10.1093/hmg/ddh019 PubMedCrossRef

Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D (2000) Abeta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408(6815):979–982PubMedCrossRef

Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu CE, Bird TD (2010) Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain 133(Pt 4):1143–1154. doi:10.1093/brain/awq033 PubMedPubMedCentralCrossRef

Jones L, Harold D, Williams J (2010a) Genetic evidence for the involvement of lipid metabolism in Alzheimer’s disease. Biochim Biophys Acta 1801(8):754–761. doi:10.1016/j.bbalip.2010.04.005 PubMedCrossRef

Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D, Pocklington A, Abraham R, Hollingworth P, Sims R, Gerrish A, Pahwa JS, Jones N, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann B, Heun R, Kolsch H, van den Bussche H, Heuser I, Peters O, Kornhuber J, Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp N, Wichmann HE, Ruther E, Carrasquillo MM, Pankratz VS, Younkin SG, Hardy J, O’Donovan MC, Owen MJ, Williams J (2010b) Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PLoS One 5(11):e13950. doi:10.1371/journal.pone.0013950 PubMedPubMedCentralCrossRef

Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JL, 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 H (2012) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368(2):107–116PubMedPubMedCentralCrossRef

Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698–712. doi:10.1038/nrd3505 PubMedCrossRef

Kawahara K, Suenobu M, Yoshida A, Koga K, Hyodo A, Ohtsuka H, Kuniyasu A, Tamamaki N, Sugimoto Y, Nakayama H (2012) Intracerebral microinjection of interleukin-4/interleukin-13 reduces beta-amyloid accumulation in the ipsilateral side and improves cognitive deficits in young amyloid precursor protein 23 mice. Neuroscience 207:243–260. doi:10.1016/j.neuroscience.2012.01.049 PubMedCrossRef

Kitazawa M, Cheng D, Tsukamoto MR, Koike MA, Wes PD, Vasilevko V, Cribbs DH, LaFerla FM (2011) Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal beta-catenin pathway function in an Alzheimer’s disease model. J Immunol 187(12):6539–6549. doi:10.4049/jimmunol.1100620 PubMedCrossRef

Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, Miller KR, Prokop S, Kettenmann H, Heppner FL (2013) Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One 8(4):e60921. doi:10.1371/journal.pone.0060921 PubMedPubMedCentralCrossRef

LaFerla FM, Green KN (2012) Animal models of Alzheimer disease. Cold Spring Harb Perspect Med. doi:10.1101/cshperspect.a006320 PubMedPubMedCentralCrossRef

Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fievet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossu P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanche H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alperovitch A, Lathrop M, Amouyel P (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41(10):1094–1099PubMedCrossRef

Lambert JC, Grenier-Boley B, Chouraki V, Heath S, Zelenika D, Fievet N, Hannequin D, Pasquier F, Hanon O, Brice A, Epelbaum J, Berr C, Dartigues JF, Tzourio C, Campion D, Lathrop M, Amouyel P (2010) Implication of the immune system in Alzheimer’s disease: evidence from genome-wide pathway analysis. J Alzheimers Dis 20(4):1107–1118. doi:10.3233/JAD-2010-100018 PubMedCrossRef

Lambrechts A, Van Troys M, Ampe C (2004) The actin cytoskeleton in normal and pathological cell motility. Int J Biochem Cell Biol 36(10):1890–1909. doi:10.1016/j.biocel.2004.01.024 PubMedCrossRef

Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39(1):151–170PubMedCrossRef

Lee CK, Weindruch R, Prolla TA (2000) Gene-expression profile of the ageing brain in mice. Nat Genet 25(3):294–297. doi:10.1038/77046 PubMedCrossRef

Lenz KM, Nugent BM, Haliyur R, McCarthy MM (2013) Microglia are essential to masculinization of brain and behavior. J Neurosci 33(7):2761–2772. doi:10.1523/jneurosci.1268-12.2013 PubMedPubMedCentralCrossRef

Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293(5534):1487–1491PubMedCrossRef

Lombardo JA, Stern EA, McLellan ME, Kajdasz ST, Hickey GA, Bacskai BJ, Hyman BT (2003) Amyloid-beta antibody treatment leads to rapid normalization of plaque-induced neuritic alterations. J Neurosci 23(34):10879–10883PubMedCrossRefPubMedCentral

Lopez-Gonzalez I, Schluter A, Aso E, Garcia-Esparcia P, Ansoleaga B, LLorens F, Carmona M, Moreno J, Fuso A, Portero-Otin M, Pamplona R, Pujol A, Ferrer I (2015) Neuroinflammatory signals in Alzheimer disease and APP/PS1 transgenic mice: correlations with plaques, tangles, and oligomeric species. J Neuropathol Exp Neurol 74(4):319–344. doi:10.1097/NEN.0000000000000176 PubMedCrossRef

Lui JH, Hansen DV, Kriegstein AR (2011) Development and evolution of the human neocortex. Cell 146(1):18–36. doi:10.1016/j.cell.2011.06.030 PubMedPubMedCentralCrossRef

Maheswaran S, Barjat H, Rueckert D, Bate ST, Howlett DR, Tilling L, Smart SC, Pohlmann A, Richardson JC, Hartkens T, Hill DL, Upton N, Hajnal JV, James MF (2009) Longitudinal regional brain volume changes quantified in normal aging and Alzheimer’s APP × PS1 mice using MRI. Brain Res 1270:19–32. doi:10.1016/j.brainres.2009.02.045 PubMedCrossRef

Marcon G, Giaccone G, Cupidi C, Balestrieri M, Beltrami CA, Finato N, Bergonzi P, Sorbi S, Bugiani O, Tagliavini F (2004) Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene. J Neuropathol Exp Neurol 63(3):199–209PubMedCrossRef

Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6:13. doi:10.12703/P6-13 PubMedPubMedCentralCrossRef

McDowell I (2001) Alzheimer’s disease: insights from epidemiology. Aging (Milan, Italy) 13(3):143–162

McGeer PL, Itagaki S, Tago H, McGeer EG (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79(1–2):195–200PubMedCrossRef

Miller JA, Horvath S, Geschwind DH (2010) Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways. Proc Natl Acad Sci USA 107(28):12698–12703. doi:10.1073/pnas.0914257107 PubMedPubMedCentralCrossRef

Minett T, Classey J, Matthews FE, Fahrenhold M, Taga M, Brayne C, Ince PG, Nicoll JA, Boche D (2016) Microglial immunophenotype in dementia with Alzheimer’s pathology. J Neuroinflammation 13(1):135–145. doi:10.1186/s12974-016-0601-z PubMedPubMedCentralCrossRef

Mirza MA, Ritzel R, Xu Y, McCullough LD, Liu F (2015) Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy. J Neuroinflammation 12:32. doi:10.1186/s12974-015-0251-6 PubMedPubMedCentralCrossRef

Mittelbronn M, Dietz K, Schluesener HJ, Meyermann R (2001) Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude. Acta Neuropathol 101(3):249–255PubMed

Mizuno T, Doi Y, Mizoguchi H, Jin S, Noda M, Sonobe Y, Takeuchi H, Suzumura A (2011) Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-beta neurotoxicity. Am J Pathol 179(4):2016–2027. doi:10.1016/j.ajpath.2011.06.011 PubMedPubMedCentralCrossRef

Moehlmann T, Winkler E, Xia X, Edbauer D, Murrell J, Capell A, Kaether C, Zheng H, Ghetti B, Haass C, Steiner H (2002) Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci USA 99(12):8025–8030. doi:10.1073/pnas.112686799 PubMedPubMedCentralCrossRef

Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW (2000) Abeta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408(6815):982–985PubMedCrossRef

Morgan D, Gordon MN, Tan J, Wilcock D, Rojiani AM (2005) Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics. J Neuropathol Exp Neurol 64(9):743–753PubMedCrossRef

Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958–969. doi:10.1038/nri2448 PubMedPubMedCentralCrossRef

Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1(5):345–347. doi:10.1038/ng0892-345 PubMedCrossRef

Mummery CJ, Patterson K, Price CJ, Ashburner J, Frackowiak RS, Hodges JR (2000) A voxel-based morphometry study of semantic dementia: relationship between temporal lobe atrophy and semantic memory. Ann Neurol 47(1):36–45PubMedCrossRef

Munoz L, Ralay Ranaivo H, Roy SM, Hu W, Craft JM, McNamara LK, Chico LW, Van Eldik LJ, Watterson DM (2007) A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer’s disease mouse model. J Neuroinflammation 4:21. doi:10.1186/1742-2094-4-21 PubMedPubMedCentralCrossRef

Netea MG, Latz E, Mills KH, O’Neill LA (2015) Innate immune memory: a paradigm shift in understanding host defense. Nat Immunol 16(7):675–679. doi:10.1038/ni.3178 PubMedCrossRef

Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, Vlachouli C, Wilkinson D, Bayer A, Games D, Seubert P, Schenk D, Holmes C (2006) Abeta species removal after Abeta42 immunization. J Neuropathol Exp Neurol 65(11):1040–1048PubMedCrossRef

Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318. doi:10.1126/science.1110647 PubMedCrossRef

Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26(40):10129–10140. doi:10.1523/jneurosci.1202-06.2006 PubMedCrossRefPubMedCentral

Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39(3):409–421PubMedCrossRef

Ohsawa K, Imai Y, Kanazawa H, Sasaki Y, Kohsaka S (2000) Involvement of Iba1 in membrane ruffling and phagocytosis of macrophages/microglia. J Cell Sci 113(Pt 17):3073–3084PubMed

Okello A, Koivunen J, Edison P, Archer HA, Turkheimer FE, Nagren K, Bullock R, Walker Z, Kennedy A, Fox NC, Rossor MN, Rinne JO, Brooks DJ (2009) Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology 73(10):754–760. doi:10.1212/WNL.0b013e3181b23564 PubMedPubMedCentralCrossRef

Orre M, Kamphuis W, Osborn LM, Melief J, Kooijman L, Huitinga I, Klooster J, Bossers K, Hol EM (2014) Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice. Neurobiol Aging 35(1):1–14. doi:10.1016/j.neurobiolaging.2013.07.008 PubMedCrossRef

Pedersen JT, Sigurdsson EM (2015) Tau immunotherapy for Alzheimer’s disease. Trends Mol Med 21(6):394–402. doi:10.1016/j.molmed.2015.03.003 PubMedCrossRef

Perry VH, Holmes C (2014) Microglial priming in neurodegenerative disease. Nat Rev Neurol 10(4):217–224. doi:10.1038/nrneurol.2014.38 PubMedCrossRef

Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6(4):193–201. doi:10.1038/nrneurol.2010.17 PubMedCrossRef

Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S, Haass C, Ghetti B, Czech C, Holscher C, Mathews PM, Jucker M (2006) Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep 7(9):940–946. doi:10.1038/sj.embor.7400784 PubMedPubMedCentralCrossRef

Rae F, Woods K, Sasmono T, Campanale N, Taylor D, Ovchinnikov DA, Grimmond SM, Hume DA, Ricardo SD, Little MH (2007) Characterisation and trophic functions of murine embryonic macrophages based upon the use of a Csf1r-EGFP transgene reporter. Dev Biol 308(1):232–246. doi:10.1016/j.ydbio.2007.05.027 PubMedCrossRef

Rasool S, Martinez-Coria H, Wu JW, LaFerla F, Glabe CG (2013) Systemic vaccination with anti-oligomeric monoclonal antibodies improves cognitive function by reducing Abeta deposition and tau pathology in 3xTg-AD mice. J Neurochem 126(4):473–482. doi:10.1111/jnc.12305 PubMedPubMedCentralCrossRef

Riley KP, Snowdon DA, Markesbery WR (2002) Alzheimer’s neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol 51(5):567–577. doi:10.1002/ana.10161 PubMedCrossRef

Riudavets MA, Bartoloni L, Troncoso JC, Pletnikova O, St George-Hyslop P, Schultz M, Sevlever G, Allegri RF (2013) Familial dementia with frontotemporal features associated with M146V presenilin-1 mutation. Brain Pathol 23(5):595–600. doi:10.1111/bpa.12051 PubMedPubMedCentralCrossRef

Roy A, Fung YK, Liu X, Pahan K (2006) Up-regulation of microglial CD11b expression by nitric oxide. J Biol Chem 281(21):14971–14980. doi:10.1074/jbc.M600236200 PubMedCrossRef

Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11(11):775–787. doi:10.1038/nri3086 PubMedCrossRef

Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR, Bapineuzumab 301 and 302 Clinical Trial Investigators (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4):322–333. doi:10.1056/NEJMoa1304839 PubMedPubMedCentralCrossRef

Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74(4):691–705. doi:10.1016/j.neuron.2012.03.026 PubMedPubMedCentralCrossRef

Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400(6740):173–177PubMedCrossRef

Schuff N, Tosun D, Insel PS, Chiang GC, Truran D, Aisen PS, Jack CR Jr, Weiner MW (2012) Nonlinear time course of brain volume loss in cognitively normal and impaired elders. Neurobiol Aging 33(5):845–855. doi:10.1016/j.neurobiolaging.2010.07.012 PubMedCrossRef

Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011a) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1(1):a006189. doi:10.1101/cshperspect.a006189 PubMedPubMedCentralCrossRef

Serrano-Pozo A, Mielke ML, Gomez-Isla T, Betensky RA, Growdon JH, Frosch MP, Hyman BT (2011b) Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol 179(3):1373–1384. doi:10.1016/j.ajpath.2011.05.047 PubMedPubMedCentralCrossRef

Serrano-Pozo A, Muzikansky A, Gomez-Isla T, Growdon JH, Betensky RA, Frosch MP, Hyman BT (2013) Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in Alzheimer disease. J Neuropathol Exp Neurol 72(6):462–471. doi:10.1097/NEN.0b013e3182933788 PubMedCrossRef

Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A (2016) The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 537(7618):50–56. doi:10.1038/nature19323 PubMedCrossRef

Shioi J, Georgakopoulos A, Mehta P, Kouchi Z, Litterst CM, Baki L, Robakis NK (2007) FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem 101(3):674–681. doi:10.1111/j.1471-4159.2006.04391.x PubMedCrossRef

Sigurdsson EM (2016) Tau immunotherapy. Neurodegener Dis 16(1–2):34–38. doi:10.1159/000440842 PubMedCrossRef

Simard AR, Soulet D, Gowing G, Julien JP, Rivest S (2006) Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49(4):489–502PubMedCrossRef

Song M, Jin J, Lim JE, Kou J, Pattanayak A, Rehman JA, Kim HD, Tahara K, Lalonde R, Fukuchi K (2011) TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflammation 8:92. doi:10.1186/1742-2094-8-92 PubMedPubMedCentralCrossRef

Spinney L (2014) Alzheimer’s disease: the forgetting gene. Nature 510(7503):26–28. doi:10.1038/510026a PubMedCrossRef

Spires-Jones TL, Mielke ML, Rozkalne A, Meyer-Luehmann M, de Calignon A, Bacskai BJ, Schenk D, Hyman BT (2009) Passive immunotherapy rapidly increases structural plasticity in a mouse model of Alzheimer disease. Neurobiol Dis 33(2):213–220. doi:10.1016/j.nbd.2008.10.011 PubMedCrossRef

Squarzoni P, Oller G, Hoeffel G, Pont-Lezica L, Rostaing P, Low D, Bessis A, Ginhoux F, Garel S (2014) Microglia modulate wiring of the embryonic forebrain. Cell Rep 8(5):1271–1279. doi:10.1016/j.celrep.2014.07.042 PubMedCrossRef

Stalder M, Phinney A, Probst A, Sommer B, Staufenbiel M, Jucker M (1999) Association of microglia with amyloid plaques in brains of APP23 transgenic mice. Am J Pathol 154(6):1673–1684PubMedPubMedCentralCrossRef

Stence N, Waite M, Dailey ME (2001) Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 33(3):256–266. doi:10.1002/1098-1136(200103)33:3<256:AID-GLIA1024>3.0.CO;2-J PubMedCrossRef

Streit WJ, Braak H, Xue QS, Bechmann I (2009) Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 118(4):475–485. doi:10.1007/s00401-009-0556-6 PubMedPubMedCentralCrossRef

Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010) A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68(10):930–941. doi:10.1016/j.biopsych.2010.06.012 PubMedCrossRef

Tollervey JR, Wang Z, Hortobagyi T, Witten JT, Zarnack K, Kayikci M, Clark TA, Schweitzer AC, Rot G, Curk T, Zupan B, Rogelj B, Shaw CE, Ule J (2011) Analysis of alternative splicing associated with aging and neurodegeneration in the human brain. Genome Res 21(10):1572–1582. doi:10.1101/gr.122226.111 PubMedPubMedCentralCrossRef

Torres-Platas SG, Comeau S, Rachalski A, Bo GD, Cruceanu C, Turecki G, Giros B, Mechawar N (2014) Morphometric characterization of microglial phenotypes in human cerebral cortex. J Neuroinflammation 11:12. doi:10.1186/1742-2094-11-12 PubMedPubMedCentralCrossRef

Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8(11):e1000527. doi:10.1371/journal.pbio.1000527 PubMedPubMedCentralCrossRef

go back to reference Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P, Antonarakis SE, Attwood J, Baertsch R, Bailey J, Barlow K, Beck S, Berry E, Birren B, Bloom T, Bork P, Botcherby M, Bray N, Brent MR, Brown DG, Brown SD, Bult C, Burton J, Butler J, Campbell RD, Carninci P, Cawley S, Chiaromonte F, Chinwalla AT, Church DM, Clamp M, Clee C, Collins FS, Cook LL, Copley RR, Coulson A, Couronne O, Cuff J, Curwen V, Cutts T, Daly M, David R, Davies J, Delehaunty KD, Deri J, Dermitzakis ET, Dewey C, Dickens NJ, Diekhans M, Dodge S, Dubchak I, Dunn DM, Eddy SR, Elnitski L, Emes RD, Eswara P, Eyras E, Felsenfeld A, Fewell GA, Flicek P, Foley K, Frankel WN, Fulton LA, Fulton RS, Furey TS, Gage D, Gibbs RA, Glusman G, Gnerre S, Goldman N, Goodstadt L, Grafham D, Graves TA, Green ED, Gregory S, Guigo R, Guyer M, Hardison RC, Haussler D, Hayashizaki Y, Hillier LW, Hinrichs A, Hlavina W, Holzer T, Hsu F, Hua A, Hubbard T, Hunt A, Jackson I, Jaffe DB, Johnson LS, Jones M, Jones TA, Joy A, Kamal M, Karlsson EK, Karolchik D, Kasprzyk A, Kawai J, Keibler E, Kells C, Kent WJ, Kirby A, Kolbe DL, Korf I, Kucherlapati RS, Kulbokas EJ, Kulp D, Landers T, Leger JP, Leonard S, Letunic I, Levine R, Li J, Li M, Lloyd C, Lucas S, Ma B, Maglott DR, Mardis ER, Matthews L, Mauceli E, Mayer JH, McCarthy M, McCombie WR, McLaren S, McLay K, McPherson JD, Meldrim J, Meredith B, Mesirov JP, Miller W, Miner TL, Mongin E, Montgomery KT, Morgan M, Mott R, Mullikin JC, Muzny DM, Nash WE, Nelson JO, Nhan MN, Nicol R, Ning Z, Nusbaum C, O’Connor MJ, Okazaki Y, Oliver K, Overton-Larty E, Pachter L, Parra G, Pepin KH, Peterson J, Pevzner P, Plumb R, Pohl CS, Poliakov A, Ponce TC, Ponting CP, Potter S, Quail M, Reymond A, Roe BA, Roskin KM, Rubin EM, Rust AG, Santos R, Sapojnikov V, Schultz B, Schultz J, Schwartz MS, Schwartz S, Scott C, Seaman S, Searle S, Sharpe T, Sheridan A, Shownkeen R, Sims S, Singer JB, Slater G, Smit A, Smith DR, Spencer B, Stabenau A, Stange-Thomann N, Sugnet C, Suyama M, Tesler G, Thompson J, Torrents D, Trevaskis E, Tromp J, Ucla C, Ureta-Vidal A, Vinson JP, Von Niederhausern AC, Wade CM, Wall M, Weber RJ, Weiss RB, Wendl MC, West AP, Wetterstrand K, Wheeler R, Whelan S, Wierzbowski J, Willey D, Williams S, Wilson RK, Winter E, Worley KC, Wyman D, Yang S, Yang SP, Zdobnov EM, Zody MC, Lander ES (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420(6915):520–562. doi:10.1038/nature01262 PubMedCrossRef Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P, Antonarakis SE, Attwood J, Baertsch R, Bailey J, Barlow K, Beck S, Berry E, Birren B, Bloom T, Bork P, Botcherby M, Bray N, Brent MR, Brown DG, Brown SD, Bult C, Burton J, Butler J, Campbell RD, Carninci P, Cawley S, Chiaromonte F, Chinwalla AT, Church DM, Clamp M, Clee C, Collins FS, Cook LL, Copley RR, Coulson A, Couronne O, Cuff J, Curwen V, Cutts T, Daly M, David R, Davies J, Delehaunty KD, Deri J, Dermitzakis ET, Dewey C, Dickens NJ, Diekhans M, Dodge S, Dubchak I, Dunn DM, Eddy SR, Elnitski L, Emes RD, Eswara P, Eyras E, Felsenfeld A, Fewell GA, Flicek P, Foley K, Frankel WN, Fulton LA, Fulton RS, Furey TS, Gage D, Gibbs RA, Glusman G, Gnerre S, Goldman N, Goodstadt L, Grafham D, Graves TA, Green ED, Gregory S, Guigo R, Guyer M, Hardison RC, Haussler D, Hayashizaki Y, Hillier LW, Hinrichs A, Hlavina W, Holzer T, Hsu F, Hua A, Hubbard T, Hunt A, Jackson I, Jaffe DB, Johnson LS, Jones M, Jones TA, Joy A, Kamal M, Karlsson EK, Karolchik D, Kasprzyk A, Kawai J, Keibler E, Kells C, Kent WJ, Kirby A, Kolbe DL, Korf I, Kucherlapati RS, Kulbokas EJ, Kulp D, Landers T, Leger JP, Leonard S, Letunic I, Levine R, Li J, Li M, Lloyd C, Lucas S, Ma B, Maglott DR, Mardis ER, Matthews L, Mauceli E, Mayer JH, McCarthy M, McCombie WR, McLaren S, McLay K, McPherson JD, Meldrim J, Meredith B, Mesirov JP, Miller W, Miner TL, Mongin E, Montgomery KT, Morgan M, Mott R, Mullikin JC, Muzny DM, Nash WE, Nelson JO, Nhan MN, Nicol R, Ning Z, Nusbaum C, O’Connor MJ, Okazaki Y, Oliver K, Overton-Larty E, Pachter L, Parra G, Pepin KH, Peterson J, Pevzner P, Plumb R, Pohl CS, Poliakov A, Ponce TC, Ponting CP, Potter S, Quail M, Reymond A, Roe BA, Roskin KM, Rubin EM, Rust AG, Santos R, Sapojnikov V, Schultz B, Schultz J, Schwartz MS, Schwartz S, Scott C, Seaman S, Searle S, Sharpe T, Sheridan A, Shownkeen R, Sims S, Singer JB, Slater G, Smit A, Smith DR, Spencer B, Stabenau A, Stange-Thomann N, Sugnet C, Suyama M, Tesler G, Thompson J, Torrents D, Trevaskis E, Tromp J, Ucla C, Ureta-Vidal A, Vinson JP, Von Niederhausern AC, Wade CM, Wall M, Weber RJ, Weiss RB, Wendl MC, West AP, Wetterstrand K, Wheeler R, Whelan S, Wierzbowski J, Willey D, Williams S, Wilson RK, Winter E, Worley KC, Wyman D, Yang S, Yang SP, Zdobnov EM, Zody MC, Lander ES (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420(6915):520–562. doi:10.1038/nature01262 PubMedCrossRef

Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ (2014) Using mice to model Alzheimer’s dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet 5:88. doi:10.3389/fgene.2014.00088 PubMedPubMedCentralCrossRef

Werling DM, Parikshak NN, Geschwind DH (2016) Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. Nat Commun 7:10717. doi:10.1038/ncomms10717 PubMedPubMedCentralCrossRef

Wilcock DM, DiCarlo G, Henderson D, Jackson J, Clarke K, Ugen KE, Gordon MN, Morgan D (2003) Intracranially administered anti-Abeta antibodies reduce beta-amyloid deposition by mechanisms both independent of and associated with microglial activation. J Neurosci 23(9):3745–3751PubMedCrossRefPubMedCentral

Wilcock DM, Munireddy SK, Rosenthal A, Ugen KE, Gordon MN, Morgan D (2004a) Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiol Dis 15(1):11–20PubMedCrossRef

Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D (2004b) Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. J Neuroinflammation 1(1):24PubMedPubMedCentralCrossRef

Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B (2015) Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol 36(10):605–613. doi:10.1016/j.it.2015.08.008 PubMedPubMedCentralCrossRef

Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, De Nardo D, Gohel TD, Emde M, Schmidleithner L, Ganesan H, Nino-Castro A, Mallmann MR, Labzin L, Theis H, Kraut M, Beyer M, Latz E, Freeman TC, Ulas T, Schultze JL (2014) Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40(2):274–288. doi:10.1016/j.immuni.2014.01.006 PubMedPubMedCentralCrossRef

Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT (2012) PPARgamma/RXRalpha-induced and CD36-mediated microglial amyloid-beta phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci 32(48):17321–17331. doi:10.1523/jneurosci.1569-12.2012 PubMedCrossRefPubMedCentral

Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53(3):337–351. doi:10.1016/j.neuron.2007.01.010 PubMedCrossRef

Yuan R, Peters LL, Paigen B (2011) Mice as a mammalian model for research on the genetics of aging. ILAR J 52(1):4–15PubMedCrossRef

Yue F, Cheng Y, Breschi A, Vierstra J, Wu W, Ryba T, Sandstrom R, Ma Z, Davis C, Pope BD, Shen Y, Pervouchine DD, Djebali S, Thurman RE, Kaul R, Rynes E, Kirilusha A, Marinov GK, Williams BA, Trout D, Amrhein H, Fisher-Aylor K, Antoshechkin I, DeSalvo G, See LH, Fastuca M, Drenkow J, Zaleski C, Dobin A, Prieto P, Lagarde J, Bussotti G, Tanzer A, Denas O, Li K, Bender MA, Zhang M, Byron R, Groudine MT, McCleary D, Pham L, Ye Z, Kuan S, Edsall L, Wu YC, Rasmussen MD, Bansal MS, Kellis M, Keller CA, Morrissey CS, Mishra T, Jain D, Dogan N, Harris RS, Cayting P, Kawli T, Boyle AP, Euskirchen G, Kundaje A, Lin S, Lin Y, Jansen C, Malladi VS, Cline MS, Erickson DT, Kirkup VM, Learned K, Sloan CA, Rosenbloom KR, Lacerda de Sousa B, Beal K, Pignatelli M, Flicek P, Lian J, Kahveci T, Lee D, Kent WJ, Ramalho Santos M, Herrero J, Notredame C, Johnson A, Vong S, Lee K, Bates D, Neri F, Diegel M, Canfield T, Sabo PJ, Wilken MS, Reh TA, Giste E, Shafer A, Kutyavin T, Haugen E, Dunn D, Reynolds AP, Neph S, Humbert R, Hansen RS, De Bruijn M, Selleri L, Rudensky A, Josefowicz S, Samstein R, Eichler EE, Orkin SH, Levasseur D, Papayannopoulou T, Chang KH, Skoultchi A, Gosh S, Disteche C, Treuting P, Wang Y, Weiss MJ, Blobel GA, Cao X, Zhong S, Wang T, Good PJ, Lowdon RF, Adams LB, Zhou XQ, Pazin MJ, Feingold EA, Wold B, Taylor J, Mortazavi A, Weissman SM, Stamatoyannopoulos JA, Snyder MP, Guigo R, Gingeras TR, Gilbert DM, Hardison RC, Beer MA, Ren B, Mouse EC (2014) A comparative encyclopedia of DNA elements in the mouse genome. Nature 515(7527):355–364. doi:10.1038/nature13992 PubMedPubMedCentralCrossRef

Zhang K, Sejnowski TJ (2000) A universal scaling law between gray matter and white matter of cerebral cortex. Proc Natl Acad Sci USA 97(10):5621–5626. doi:10.1073/pnas.090504197090504197 PubMedPubMedCentralCrossRef

Zotova E, Holmes C, Johnston D, Neal JW, Nicoll JA, Boche D (2011) Microglial alterations in human Alzheimer’s disease following Abeta42 immunization. Neuropathol Appl Neurobiol 37(5):513–524. doi:10.1111/j.1365-2990.2010.01156.x PubMedCrossRef

Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S, Neal JW, Love S, Nicoll JA, Boche D (2013) Inflammatory components in human Alzheimer’s disease and after active amyloid-beta42 immunization. Brain 136(Pt 9):2677–2696. doi:10.1093/brain/awt210 PubMedCrossRef

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Innate immunity in Alzheimer’s disease: the relevance of animal models?

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

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