ISSN 1007-7626 CN 11-3870 / Q http/ /cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology 2015 7 317 689 ~ 693 DOI10 13865 /j cnki cjbmb 2015 07 06 * 350117 AD β Aβ tau neurobrillary tangles β tau AD AD -1β -18 Q189 Alzheimers Disease and Inflammatory Regulation ZHAO Dong-YueCHEN Jin-FengCHEN Qi * Southern Biomedical Research Center at Fujian Normal UniversityFuzhou 350117China Abstract Alzheimers disease ADis a devastating neurodegenerative disease characterized by extracellular deposition of amyloid-βaβplaques and intra-cellular accumulation of hyper-phosphorylated tau protein resulting in NFTs neurobrillary tangles The Aβ and tau hypotheses postulated by its hallmark are not sufficient in explaining all the features of AD Currently inflammation and tissue injury caused by inflammasome have attracted extensive attention in the field of pathogenesis AD This review will give a brief introduction regarding how inflammasome is to be activated and assembled as well as its relation to the highly expressed inflammatory moleculeswhich will offer to a new break-through in pathological mechanism and therapeutic targets of AD Key words Alzheimers diseaseinammasomesinterleukin-1βinterleukin-18 Alzheimers diseasead β 4 AD amyloid-βaβ Aβ 5 tau AD neurobrillary tangles 1 0 38 AD 4 AD 2050 AD 2014-10-13 2015-02-11 1 15 2 Aβ tau β tau AD AD Republic of China No WKJ-FJ-28 Aβ * Corresponding author Tel0591-22868832 3 Aβ tau AD E-mail191716564@ qq com No WKJ-FJ-28 * Tel0591-22868832E-mail191716564@ qq com ReceivedOctober 132014AcceptedFebruary 112015 Supported by National Health and Family Planning Commission of People
690 31 PYD ASC ASC Caspase-1 24 APP /PS1 CARD pro-caspase-1 pro- NLRP3 AD 6 AD caspase-1 caspase-1 7 NLRP3 NLRP3 8 AD NLRP3 NLRP3 AD 2 AD AD 9 AD AD AD AD 19 1 IL- 1β IL-6 TNFα α inflammasomes 20 21 caspase-1 Caspase-1-1β pro-interleukin- 1β -18 pro-interleukin -18-1β IL-1β -18 IL- 18 10 2 1-1β NLRsNOD1 NOD2 NLRP3 NLRC4 21-1βIL-1β non-nlrs AIM2 RIG-I IFI16 adapter protein caspase recruitment IL-1β IL-1β domain CARD apoptosisassociated speck-like protein containing a CARD КB IL-1β IL-1β NFКB ASC caspase-1 11 MAPK-p38 BACE1 ASC Naip5 APP Aβ 12 IL-1β caspase-1 12 NLRC4 NLRs IL-1β IL-6 IL-18 NO NLRs 3 IL- 1β APP Aβ 22 NACHT domain IL-1β S100B PYD CARD BIP 13 NLRP3 TLR APP 22 IL-1β tau NLRP3 14 MAPK-p38 23 AD PAMPs IL-1β DAMPs tau 15 16 NLRP3 NACHT domain Aβ ATP 17 18 PYD ASC-N NLRP2 NLRP2
7 691 25 NLRP3 Aβ 26 NLRP3 3 AD 27 NLRC4 IL-1β 28 ASC NLRC4 IL-1β IL-6 TNFα 37 38 28 39 IL-1β IL-1β 28 BACE1 Aβ 29 Liu 28 2 2-18 NLRC4 IL-1β -18 IL-18 ASC NLRC4 IL-18 NLRC4 ASC IL-1 IL-1β 28 AD IL-18 proil-18 NLRC4 ASC NLRC4 IL-18 IL-1β AD IL-1β 30 IL-18 NLRC4 40 AD 31 IL-18 IL-1β mrna APP AD 41 Aβ 42 Aβ 32 AD AD BACE1 Aβ IL-18 43 tau 44 33 Ⅱ AD 45 34 IL-18 APP 46 BACE1 PS1 N- 2 γ 33 AD IL- 18 3GSK-3 IL-1β 5Cdk5 tau BACE1 35 Aβ IL-18 AD 42 28 Aβ AD 47 48 IL-18 IL-1β p60 IL-18 IL-1β NLRP3 IL-1β serine palmitoyltransferasespt IL-18 36 IL-18 IL-1β SPT ATP IL-1β TNFα 29 NLRP2 AD IL-1β IL-18 12 SPT Aβ 42 tau pannexin1 ATP 49 IL-1β IL-18 12 IL- AD 1β IL-18
692 31 4-1β 13Schroder KTschopp J The inflammasomesj -18 1406 821-832 14Huang TTChong KYOjcius DMet al IL-1β IL-18 AD Cell Mol Med2008126A 2255-2262 AD of neurodegeneration J 627 AD References 1Huang YMucke L Alzheimer mechanisms and therapeutic strategies J Cell20121486 1204-1222 2Alzheimer s Association 2012 Alzheimer s disease facts and figures J Alzheimers Dement201282 131-168 3Batsch NMittelman M World Alzheimer Report 2012 Overcoming the stigma of dementiam LondonAlzheimers Disease International2012 4Aizenstein HJNebes RDSaxton JAet al Frequent amyloid deposition without significant cognitive impairment among the elderly J Arch Neurol200865111509-1517 5Johnston HBoutin HAllan S Assessing the contribution of inflammation in models of Alzheimers diseasej Biochem Soc Trans2011394 886-890 6Thomas TNadackal TGThomas K Aspirin and non-steroidal anti-inflammatory drugs inhibit amyloid-β aggregation J Neuroreport200112153263-3267 7Sudduth TLSchmitt FANelson PTet al Neuroinflammatory phenotype in early Alzheimers diseasej Neurobiol Aging 2013344 1051-1059 8Hollingworth PHarold DJones L et al Alzheimers disease geneticscurrent knowledge and future challengesj Int J Geriatr Psychiatry2011268 793-802 9Liu LMartin RChan C Palmitate-activated astrocytes via serine palmitoyltransferase increase BACE1 in primary neurons by sphingomyelinasesj Neurobiol Aging201334 2 540-550 10Schmidt RLLenz LL Distinct licensing of IL-18 and IL-1β secretion in response to NLRP3 inflammasome activationj PLoS One201279 e45186 11Martinon FMayor ATschopp J The inflammasomes 12Minkiewicz JRivero Vaccari JPKeane RW Human astrocytes express a novel NLRP2 inflammasome J Glia2013617 1113-1121 Cell2010 Hirsutella sinensis mycelium suppresses interleukin-1β and interleukin-18 secretion by inhibiting both canonical and non-canonical inflammasomes J Sci Rep201331374 15Salminen AOjala JSuuronen Tet al Amyloid-β oligomers set fire to inflammasomes and induce Alzheimers pathology J J 16Mathew ALindsley TASheridan Aet al Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern DAMPfamily and possible trigger guardians of the bodyj Annu Rev immunol200927229-265 J Alzheimers Dis2012303 617-17Lightfield KLPersson JTrinidad NJet al Differential requirements for NAIP5 in activation of the NLRC4 inflammasome J Infect Immun2011794 1606-1614 18van de Veerdonk FLNetea MGDinarello CAet al Inflammasome activation and IL-1β and IL-18 processing during infection J Trends Immunol2011323 110-116 19Tansey MGMcCoy MKFrank-Cannon TC Neuroinflammatory mechanisms in Parkinson s disease potential environmental triggerspathwaysand targets for early therapeutic intervention J Exp Neurol20072081 1-25 20Schultzberg MLindberg CAronsson F et al Inflammation in the nervous system- physiological and pathophysiological aspects J Physiol Behav2007921-2 121-128 21Das SMishra MKGhosh Jet al Japanese Encephalitis Virus infection induces IL-18 and IL-1β in microglia and astrocytes Correlation with in vitro cytokine responsiveness of glial cells and subsequent neuronal death J J Neuroimmunol20081951-260-72 22Li CZhao RGao Ket al Astrocytes implications for neuroinflammatory pathogenesis of Alzheimers diseasej Curr Alzheimer Res201181 67-80 23Griffin WSLiu LLi Yet al Interleukin-1 mediates Alzheimer and Lewy body pathologies J J Neuroinflammation 200631 5 24Kitazawa MCheng DTsukamoto Met al Blocking IL-1 signaling rescues cognitionattenuates tau pathologyand restores neuronal beta-catenin pathway function in an Alzheimers disease model J J Immunol187126539-6549 25Heneka MTKummer MPStutz A et al NLRP3 is activated in Alzheimer /s disease and contributes to pathology in APP /PS1 mice J Nature20134937434674-678 26De Nardo DLatz E NLRP3 inflammasomes link inflammation and metabolic disease J Trends Immunol2011 328 373-379 27Shi JQZhang CCSun XL et al Antimalarial drug artemisinin
7 693 extenuates amyloidogenesis and neuroinflammation in APPswe / PS1dE9 transgenic mice via inhibition of nuclear factor κb and NLRP3 inflammasome activation J CNS Neurosci Ther 2013 194 262-268 28Liu LChan C IPAF inflammasome is involved in interleukin- 1β production from astrocytesinduced by palmitate implications for Alzheimer s DiseaseJ Neurobiol Aging 2014352 309-321 29Liu LMartin RKohler Get al Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytesj Exp Neurol2013248 482-490 30Mathew ALindsley TASheridan Aet al Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern DAMPfamily and possible trigger of neurodegeneration J J Alzheimers Dis2012303 617-627 31Yu JTTan LSong JHet al Interleukin-18 promoter polymorphisms and risk of late onset Alzheimers diseasej Brain Res20091253169-175 32Ojala JAlafuzoff IHerukka SKet al Expression of interleukin-18 is increased in the brains of Alzheimers disease patients J Neurobiol Aging2009302 198-209 33Bossù PCiaramella ASalani F et al Interleukin-18 produced by peripheral blood cells is increased in Alzheimers disease and correlates with cognitive impairmentj Brain Behav Immun 2008224 487-492 34Sutinen EMPirttila TAnderson Get al Pro-inflammatory interleukin-18 increases Alzheimers disease-associated amyloidbeta production in human neuron-like cells J J Neuroinflammation20129199 35Ojala JOSutinen EMSalminen Aet al Interleukin-18 increases expression of kinases involved in tau phosphorylation in SH-SY5Y neuroblastoma cells J J Neuroimmunol2008205 1 86-93 36Schmidt RLLenz LL Distinct licensing of IL-18 and IL-1β secretion in response to NLRP3 inflammasome activationj PLoS One201279 e45186 47Gupta SKnight AGGupta Set al Saturated long-chain fatty acids activate inflammatory signaling in astrocytes J J Neurochem20121206 1060-1071 38Borges MCVinolo MACrisma ARet al High-fat diet blunts activation of the nuclear factor-κb signaling pathway in lipopolysaccharide-stimulated peritoneal macrophages of Wistar rats J Nutrition2013292 443-449 39Cho HWu MZhang Let al Signaling dynamics of palmitateinduced ER stress responses mediated by ATF4 in HepG2 cells J BMC Syst Biol201379 40Luo XYang YShen Tet al Docosahexaenoic acid ameliorates palmitate-induced lipid accumulation and inflammation through repressing NLRC4 inflammasome activation in HepG2 cells J Nutr Metab Lond 201291 34 41Julien CTremblay CPhivilay A et al High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model J Neurobiol Aging2010319 1516-1531 42Maesako MUemura KKubota Met al Environmental enrichment ameliorated high-fat diet-induced Aβ deposition and memory deficit in APP transgenic micej Neurobiol Aging 2012335 1011 43Patil SSheng LMasserang Aet al Palmitic acid-treated astrocytes induce BACE1 upregulation and accumulation of C- terminal fragment of APP in primary cortical neurons J Neurosci Lett20064061 55-59 44Patil SMelrose JChan C Involvement of astroglial ceramide in palmitic acid-induced Alzheimer-like changes in primary neurons J Eur J Neurosci2007268 2131-2141 45Karmi AIozzo PViljanen Aet al Increased brain fatty acid uptake in metabolic syndrome J Diabetes201059 9 2171-2177 46Di Paolo GKim TW Linking lipids to Alzheimers disease cholesterol and beyondj Nat Rev Neurosci201112 5 284-296 47Patil SChan C Palmitic and stearic fatty acids induce Alzheimer-like hyperphosphorylation of tau in primary rat cortical neurons J Neurosci Lett20053843 288-293 48Qin JBerdyshev EGoya Jet al Neurons and oligodendrocytes recycle sphingosine 1- phosphate to ceramide significance for apoptosis and multiple sclerosis J J Biol Chem20102851914134-14143 49Geekiyanage HUpadhye AChan C Inhibition of serine palmitoyltransferase reduces Aβ and tau hyperphosphorylation in a murine modela safe therapeutic strategy for Alzheimer s disease J Neurobiol Aging2013348 2037-2051