Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study

Authors: David H Cribbs, Nicole C Berchtold, Victoria Perreau, Paul D Coleman, Joseph Rogers, Andrea J Tenner, Carl W Cotman

Published in: Journal of Neuroinflammation | Issue 1/2012

Login to get access

Abstract

Background

This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD).

Methods

In a well-powered microarray study of young (20 to 59 years), aged (60 to 99 years), and AD (74 to 95 years) cases, gene responses were assessed in the hippocampus, entorhinal cortex, superior frontal gyrus, and post-central gyrus.

Results

Several novel concepts emerge. First, immune/inflammation-related genes showed major changes in gene expression over the course of cognitively normal aging, with the extent of gene response far greater in aging than in AD. Of the 759 immune-related probesets interrogated on the microarray, approximately 40% were significantly altered in the SFG, PCG and HC with increasing age, with the majority upregulated (64 to 86%). In contrast, far fewer immune/inflammation genes were significantly changed in the transition to AD (approximately 6% of immune-related probesets), with gene responses primarily restricted to the SFG and HC. Second, relatively few significant changes in immune/inflammation genes were detected in the EC either in aging or AD, although many genes in the EC showed similar trends in responses as in the other brain regions. Third, immune/inflammation genes undergo gender-specific patterns of response in aging and AD, with the most pronounced differences emerging in aging. Finally, there was widespread upregulation of genes reflecting activation of microglia and perivascular macrophages in the aging brain, coupled with a downregulation of select factors (TOLLIP, fractalkine) that when present curtail microglial/macrophage activation. Notably, essentially all pathways of the innate immune system were upregulated in aging, including numerous complement components, genes involved in toll-like receptor signaling and inflammasome signaling, as well as genes coding for immunoglobulin (Fc) receptors and human leukocyte antigens I and II.

Conclusions

Unexpectedly, the extent of innate immune gene upregulation in AD was modest relative to the robust response apparent in the aged brain, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages, perhaps even in the preclinical stage, of AD. Ultimately, our data suggest that an important strategy to maintain cognitive health and resilience involves reducing chronic innate immune activation that should be initiated in late midlife.
Appendix
Available only for authorised users
Literature
1.
Rogers J, Webster S, Lue LF, Brachova L, Civin WH, Emmerling M, Shivers B, Walker D, McGeer P: Inflammation and Alzheimer’s disease pathogenesis. Neurobiol Aging 1996, 17:681–686.PubMedCrossRef
2.
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, et al.: Inflammation and Alzheimer's disease. Neurobiol Aging 2000, 21:383–421.PubMedPubMedCentralCrossRef
3.
McGeer PL, Rogers J, McGeer EG: Inflammation, anti-inflammatory agents and Alzheimer disease: the last 12 years. J Alzheimers Dis 2006, 9:271–276.PubMed
4.
Wyss-Coray T: Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 2006, 12:1005–1015.PubMed
5.
McGeer PL, McGeer EG: NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging 2007, 28:639–647.PubMedCrossRef
6.
Heneka MT, O'Banion MK: Inflammatory processes in Alzheimer's disease. J Neuroimmunol 2007, 184:69–91.PubMedCrossRef
7.
Qiao X, Cummins DJ, Paul SM: Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur J Neurosci 2001, 14:474–482.PubMedCrossRef
8.
Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE: Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis 2003, 14:133–145.PubMedCrossRef
9.
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.PubMedCrossRef
10.
McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, Das P, Golde TE, LaFerla FM, Oddo S, Blesch A, Tansey MG: Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis 2009, 34:163–177.PubMedPubMedCentralCrossRef
11.
DiCarlo G, Wilcock D, Henderson D, Gordon M, Morgan D: Intrahippocampal LPS injections reduce Abeta load in APP + PS1 transgenic mice. Neurobiol Aging 2001, 22:1007–1012.PubMedCrossRef
12.
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.PubMedPubMedCentralCrossRef
13.
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.PubMedCentralCrossRefPubMed
14.
Launer LJ, Hoes AW, Ott A, Hofman A, Breteler MM, Stricker BH, in 't Veld BA: NSAIDs and incident Alzheimer's disease. The Rotterdam Study. Neurobiol Aging 1998, 19:607–611.PubMedCrossRef
15.
Arvanitakis Z, Grodstein F, Bienias JL, Schneider JA, Wilson RS, Kelly JF, Evans DA, Bennett DA: Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology. Neurology 2008, 70:2219–2225.PubMedCrossRef
16.
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.PubMed
17.
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.PubMed
18.
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.PubMedCrossRef
19.
Breitner JC, Zandi PP: Do nonsteroidal antiinflammatory drugs reduce the risk of Alzheimer's disease? N Engl J Med 2001, 345:1567–1568.PubMedCrossRef
20.
Aisen PS: The inflammatory hypothesis of Alzheimer disease: dead or alive? Alzheimer Dis Assoc Disord 2008, 22:4–5.PubMedCrossRef
21.
Meinert CL, McCaffrey LD, Breitner JC: Alzheimer's Disease anti-inflammatory prevention trial: design, methods, and baseline results. Alzheimers Dement 2009, 5:93–104.PubMedPubMedCentralCrossRef
22.
Breitner JC, Haneuse SJ, Walker R, Dublin S, Crane PK, Gray SL, Larson EB: Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology 2009, 72:1899–1905.PubMedPubMedCentralCrossRef
23.
Arends YM, Duyckaerts C, Rozemuller JM, Eikelenboom P, Hauw JJ: Microglia, amyloid and dementia in Alzheimer disease. A correlative study. Neurobiol Aging 2000, 21:39–47.PubMedCrossRef
24.
Hoozemans JJ, van Haastert ES, Veerhuis R, Arendt T, Scheper W, Eikelenboom P, Rozemuller AJ: Maximal COX-2 and ppRb expression in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia in Alzheimer's disease. J Neuroinflammation 2005, 2:27.PubMedPubMedCentralCrossRef
25.
Vehmas AK, Kawas CH, Stewart WF, Troncoso JC: Immune reactive cells in senile plaques and cognitive decline in Alzheimer's disease. Neurobiol Aging 2003, 24:321–331.PubMedCrossRef
26.
Hoozemans JJ, Veerhuis R, Rozemuller JM, Eikelenboom P: Soothing the inflamed brain: effect of non-steroidal anti-inflammatory drugs on Alzheimer's disease pathology. CNS Neurol Disord Drug Targets 2011, 10:57–67.PubMedCrossRef
27.
Eikelenboom P, Veerhuis R, van Exel E, Hoozemans JJ, Rozemuller AJ, van Gool WA: The early involvement of the innate immunity in the pathogenesis of late-onset Alzheimer's disease: neuropathological, epidemiological and genetic evidence. Curr Alzheimer Res 2011, 8:142–150.PubMedCrossRef
28.
Berchtold NC, Cribbs DH, Coleman PD, Rogers J, Head E, Kim R, Beach T, Miller C, Troncoso J, Trojanowski JQ, Zielke HR, Cotman CW: Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc Natl Acad Sci USA 2008, 105:15605–15610.PubMedPubMedCentralCrossRef
29.
Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH: Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005, 25:9275–9284.PubMedCrossRef
30.
Perry VH, Cunningham C, Holmes C: Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 2007, 7:161–167.PubMedCrossRef
31.
Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH: Systemic inflammation and disease progression in Alzheimer disease. Neurology 2009, 73:768–774.PubMedPubMedCentralCrossRef
32.
33.
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP: Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 2003, 4:249–264.PubMedCrossRef
34.
35.
36.
37.
Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL, Styren SD, Civin WH, Brachova L, Bradt B, Ward P, Lieberburg I: Complement activation by beta-amyloid in Alzheimer disease. Proc Natl Acad Sci USA 1992, 89:10016–10020.PubMedPubMedCentralCrossRef
38.
39.
Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, Heine H, Penke B, Neumann H, Fassbender K: LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide. Brain 2005, 128:1778–1789.PubMedCrossRef
40.
Fassbender K, Walter S, Kuhl S, Landmann R, Ishii K, Bertsch T, Stalder AK, Muehlhauser F, Liu Y, Ulmer AJ, Rivest S, Lentschat A, Gulbins E, Jucker M, Staufenbiel M, Brechtel K, Walter J, Multhaup G, Penke B, Adachi Y, Hartmann T, Beyreuther K: The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J 2004, 18:203–205.PubMed
41.
Bate C, Veerhuis R, Eikelenboom P, Williams A: Microglia kill amyloid-beta1–42 damaged neurons by a CD14-dependent process. Neuroreport 2004, 15:1427–1430.PubMedCrossRef
42.
Chen K, Iribarren P, Hu J, Chen J, Gong W, Cho EH, Lockett S, Dunlop NM, Wang JM: Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. J Biol Chem 2006, 281:3651–3659.PubMedCrossRef
43.
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.PubMedPubMedCentralCrossRef
44.
Udan ML, Ajit D, Crouse NR, Nichols MR: Toll-like receptors 2 and 4 mediate Abeta(1–42) activation of the innate immune response in a human monocytic cell line. J Neurochem 2008, 104:524–533.PubMed
45.
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.PubMedPubMedCentralCrossRef
46.
Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A, Siler DA, Markesbery WR, Arumugam TV, Mattson MP: Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol 2008, 213:114–121.PubMedPubMedCentralCrossRef
47.
Landreth GE, Reed-Geaghan EG: Toll-like receptors in Alzheimer's disease. Curr Top Microbiol Immunol 2009, 336:137–153.PubMedPubMedCentral
48.
Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE: CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci 2009, 29:11982–11992.PubMedPubMedCentralCrossRef
49.
Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT: The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 2008, 9:857–865.PubMedPubMedCentralCrossRef
50.
Tenner AJ: Complement in Alzheimer's disease: opportunities for modulating protective and pathogenic events. Neurobiol Aging 2001, 22:849–861.PubMedCrossRef
51.
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.PubMedPubMedCentralCrossRef
52.
Rogers J, Li R, Mastroeni D, Grover A, Leonard B, Ahern G, Cao P, Kolody H, Vedders L, Kolb WP, Sabbagh M: Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes. Neurobiol Aging 2006, 27:1733–1739.PubMedCrossRef
53.
54.
55.
Eikelenboom P, Stam FC: Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol 1982, 57:239–242.PubMedCrossRef
56.
Eikelenboom P, Veerhuis R: The role of complement and activated microglia in the pathogenesis of Alzheimer's disease. Neurobiol Aging 1996, 17:673–680.PubMedCrossRef
57.
Webster S, Lue LF, Brachova L, Tenner AJ, McGeer PL, Terai K, Walker DG, Bradt B, Cooper NR, Rogers J: Molecular and cellular characterization of the membrane attack complex, C5b-9, in Alzheimer's disease. Neurobiol Aging 1997, 18:415–421.PubMedCrossRef
58.
Fonseca MI, Ager RR, Chu SH, Yazan O, Sanderson SD, LaFerla FM, Taylor SM, Woodruff TM, Tenner AJ: Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J Immunol 2009, 183:1375–1383.PubMedPubMedCentralCrossRef
59.
Tacnet-Delorme P, Chevallier S, Arlaud GJ: Beta-amyloid fibrils activate the C1 complex of complement under physiological conditions: evidence for a binding site for A beta on the C1q globular regions. J Immunol 2001, 167:6374–6381.PubMedCrossRef
60.
Aiyaz M, Lupton MK, Proitsi P, Powell JF, Lovestone S: Complement activation as a biomarker for Alzheimer's disease. Immunobiology 2012, 217:204–215.PubMedCrossRef
61.
Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004, 5:987–995.PubMedCrossRef
62.
63.
64.
Zedler S, Faist E: The impact of endogenous triggers on trauma-associated inflammation. Curr Opin Crit Care 2006, 12:595–601.PubMedCrossRef
65.
Ehrchen JM, Sunderkotter C, Foell D, Vogl T, Roth J: The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol 2009, 86:557–566.PubMedCrossRef
66.
Pineau I, Lacroix S: Endogenous signals initiating inflammation in the injured nervous system. Glia 2009, 57:351–361.PubMedCrossRef
67.
Bianchi ME: DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007, 81:1–5.PubMedCrossRef
68.
Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MA, Nacken W, Foell D, van der Poll T, Sorg C, Roth J: Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med 2007, 13:1042–1049.PubMedCrossRef
69.
Goyette J, Geczy CL: Inflammation-associated S100 proteins: new mechanisms that regulate function. Amino Acids 2011, 41:821–842.PubMedCrossRef
70.
Lehnardt S: Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 2010, 58:253–263.PubMed
71.
Arroyo DS, Soria JA, Gaviglio EA, Rodriguez-Galan MC, Iribarren P: Toll-like receptors are key players in neurodegeneration. Int Immunopharmacol 2011, 11:1415–1421.PubMedPubMedCentralCrossRef
72.
Tschopp J, Schroder K: NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat Rev Immunol 2010, 10:210–215.PubMedCrossRef
73.
74.
Kufer TA, Sansonetti PJ: NLR functions beyond pathogen recognition. Nat Immunol 2011, 12:121–128.PubMedCrossRef
75.
Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE: Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression. Brain Pathol 1998, 8:65–72.PubMedCrossRef
76.
Griffin WS, Mrak RE: Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease. J Leukoc Biol 2002, 72:233–238.PubMedPubMedCentral
77.
Rogers J, Mastroeni D, Leonard B, Joyce J, Grover A: Neuroinflammation in Alzheimer's disease and Parkinson's disease: are microglia pathogenic in either disorder? Int Rev Neurobiol 2007, 82:235–246.PubMedCrossRef
78.
Griffin WS, Nicoll JA, Grimaldi LM, Sheng JG, Mrak RE: The pervasiveness of interleukin-1 in Alzheimer pathogenesis: a role for specific polymorphisms in disease risk. Exp Gerontol 2000, 35:481–487.PubMedPubMedCentralCrossRef
79.
Sutterwala FS, Ogura Y, Flavell RA: The inflammasome in pathogen recognition and inflammation. J Leukoc Biol 2007, 82:259–264.PubMedCrossRef
80.
Gao HM, Liu B, Zhang W, Hong JS: Novel anti-inflammatory therapy for Parkinson's disease. Trends Pharmacol Sci 2003, 24:395–401.PubMedCrossRef
81.
Mandrekar-Colucci S, Landreth GE: Microglia and inflammation in Alzheimer's disease. CNS Neurol Disord Drug Targets 2010, 9:156–167.PubMedCrossRef
82.
Okun E, Mattson MP, Arumugam TV: Involvement of Fc receptors in disorders of the central nervous system. Neuromolecular Med 2010, 12:164–178.PubMedCrossRef
83.
Peress NS, Fleit HB, Perillo E, Kuljis R, Pezzullo C: Identification of Fc gamma RI, II and III on normal human brain ramified microglia and on microglia in senile plaques in Alzheimer's disease. J Neuroimmunol 1993, 48:71–79.PubMedCrossRef
84.
Nimmerjahn F, Ravetch JV: Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 2008, 8:34–47.PubMedCrossRef
85.
van Lent PL, Grevers LC, Schelbergen R, Blom A, Geurts J, Sloetjes A, Vogl T, Roth J, van den Berg WB: S100A8 causes a shift toward expression of activatory Fcgamma receptors on macrophages via toll-like receptor 4 and regulates Fcgamma receptor expression in synovium during chronic experimental arthritis. Arthritis Rheum 2010, 62:3353–3364.PubMedCrossRef
86.
Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, Botti P, Bacon KB, Feng L: Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA 1998, 95:10896–10901.PubMedPubMedCentralCrossRef
87.
Moestrup SK, Moller HJ: CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med 2004, 36:347–354.PubMedCrossRef
88.
Fabriek BO, Dijkstra CD, van den Berg TK: The macrophage scavenger receptor CD163. Immunobiology 2005, 210:153–160.PubMedCrossRef
89.
Philippidis P, Mason JC, Evans BJ, Nadra I, Taylor KM, Haskard DO, Landis RC: Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circ Res 2004, 94:119–126.CrossRefPubMed
90.
Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP: Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 2006, 3:27.PubMedPubMedCentralCrossRef
91.
McGeer PL, Kawamata T, Walker DG, Akiyama H, Tooyama I, McGeer EG: Microglia in degenerative neurological disease. Glia 1993, 7:84–92.PubMedCrossRef
92.
Popovic M, Caballero-Bleda M, Puelles L, Popovic N: Importance of immunological and inflammatory processes in the pathogenesis and therapy of Alzheimer's disease. Int J Neurosci 1998, 95:203–236.PubMedCrossRef
93.
Perry VH: A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation. J Neuroimmunol 1998, 90:113–121.PubMedCrossRef
94.
O'Keefe GM, Nguyen VT, Benveniste EN: Regulation and function of class II major histocompatibility complex, CD40, and B7 expression in macrophages and microglia: Implications in neurological diseases. J Neurovirol 2002, 8:496–512.PubMedCrossRef
95.
Cuello AC, Ferretti MT, Leon WC, Iulita MF, Melis T, Ducatenzeiler A, Bruno MA, Canneva F: Early-stage inflammation and experimental therapy in transgenic models of the Alzheimer-like amyloid pathology. Neurodegener Dis 2010, 7:96–98.PubMedCrossRef
96.
Wiendl H, Feger U, Mittelbronn M, Jack C, Schreiner B, Stadelmann C, Antel J, Brueck W, Meyermann R, Bar-Or A, Kieseier BC, Weller M: Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity. Brain 2005, 128:2689–2704.PubMedCrossRef
97.
McGeer EG, McGeer PL: Innate immunity in Alzheimer's disease: a model for local inflammatory reactions. Mol Interv 2001, 1:22–29.PubMed
98.
Nguyen MD, Julien JP, Rivest S: Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat Rev Neurosci 2002, 3:216–227.PubMedCrossRef
99.
Perry VH, Newman TA, Cunningham C: The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci 2003, 4:103–112.PubMedCrossRef
100.
Turrin NP, Rivest S: Innate immune reaction in response to seizures: implications for the neuropathology associated with epilepsy. Neurobiol Dis 2004, 16:321–334.PubMedCrossRef
101.
Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T: Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA 2003, 100:8514–8519.PubMedPubMedCentralCrossRef
102.
103.
Abe O, Yamasue H, Yamada H, Masutani Y, Kabasawa H, Sasaki H, Takei K, Suga M, Kasai K, Aoki S, Ohtomo K: Sex dimorphism in gray/white matter volume and diffusion tensor during normal aging. NMR Biomed 2010, 23:446–458.PubMedCrossRef
104.
Taki Y, Kinomura S, Sato K, Goto R, Kawashima R, Fukuda H: A longitudinal study of gray matter volume decline with age and modifying factors. Neurobiol Aging 2011, 32:907–915.PubMedCrossRef
105.
Gong G, Rosa-Neto P, Carbonell F, Chen ZJ, He Y, Evans AC: Age- and gender-related differences in the cortical anatomical network. J Neurosci 2009, 29:15684–15693.PubMedPubMedCentralCrossRef
106.
107.
Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T: The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 2008, 118:2190–2199.PubMedPubMedCentral
108.
Jaeger PA, Pickford F, Sun CH, Lucin KM, Masliah E, Wyss-Coray T: Regulation of amyloid precursor protein processing by the Beclin 1 complex. PLoS One 2010, 5:e11102.PubMedPubMedCentralCrossRef
109.
Jaeger PA, Wyss-Coray T: Beclin 1 complex in autophagy and Alzheimer disease. Arch Neurol 2010, 67:1181–1184.PubMedCrossRef
110.
Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K: Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cell Physiol Biochem 2007, 20:947–956.PubMedCrossRef
111.
Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ: Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 2010, 9:119–128.PubMedPubMedCentralCrossRef
112.
Heister D, Brewer JB, Magda S, Blennow K, McEvoy LK: Predicting MCI outcome with clinically available MRI and CSF biomarkers. Neurology 2011, 77:1619–1628.PubMedPubMedCentralCrossRef
113.
Keller M, Ruegg A, Werner S, Beer HD: Active caspase-1 is a regulator of unconventional protein secretion. Cell 2008, 132:818–831.PubMedCrossRef
114.
115.
116.
Frost B, Diamond MI: Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 2010, 11:155–159.PubMed
117.
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 Neurosci 2006, 9:917–924.PubMedCrossRef
118.
Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA, Weeber EJ, Bickford PC, Gemma C: CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci 2011, 31:16241–16250.PubMedCrossRef
119.
Vasilevko V, Passos GF, Quiring D, Head E, Kim RC, Fisher M, Cribbs DH: Aging and cerebrovascular dysfunction: contribution of hypertension, cerebral amyloid angiopathy, and immunotherapy. Ann NY Acad Sci 2010, 1207:58–70.PubMedPubMedCentralCrossRef
120.
121.
Afagh A, Cummings BJ, Cribbs DH, Cotman CW, Tenner AJ: Localization and cell association of C1q in Alzheimer's disease brain. Exp Neurol 1996, 138:22–32.PubMedCrossRef
122.
McGeer EG, McGeer PL: Chronic inflammation in Alzheimer's disease offers therapeutic opportunities. Expert Rev Neurother 2001, 1:53–60.PubMedCrossRef
123.
Breitner JC, Baker LD, Montine TJ, Meinert CL, Lyketsos CG, Ashe KH, Brandt J, Craft S, Evans DE, Green RC, Ismail MS, Martin BK, Mullan MJ, Sabbagh M, Tariot PN, ADAPT Research Group: Extended results of the Alzheimer's disease anti-inflammatory prevention trial. Alzheimers Dement 2011, 7:402–411.PubMedPubMedCentralCrossRef
124.
Tong L, Balazs R, Soiampornkul R, Thangnipon W, Cotman CW: Interleukin-1 beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol Aging 2008, 29:1380–1393.PubMedCrossRef
125.
Metadata
Title
Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study
Authors
David H Cribbs
Nicole C Berchtold
Victoria Perreau
Paul D Coleman
Joseph Rogers
Andrea J Tenner
Carl W Cotman
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-179

Other articles of this Issue 1/2012

Journal of Neuroinflammation 1/2012 Go to the issue

Research

Anti-inflammatory effect of simvastatin in an experimental model of spinal cord trauma: involvement of PPAR-α

Research

Increase of arginase activity in old apolipoprotein-E deficient mice under Western diet associated with changes in neurovascular unit

Research

Histamine modulates microglia function

Review

Inflammatory monocytes and the pathogenesis of viral encephalitis

Research

Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway

Research

Rod microglia: elongation, alignment, and coupling to form trains across the somatosensory cortex after experimental diffuse brain injury