阿尔茨海默病中炎症反应的研究进展
|
摘要
阿尔茨海默病(AD)是常见的痴呆类型之一,AD的认知功能损害和行为损害严重危害老年人的健康。关于AD的发病机制,存在多种学说。越来越多的研究表明,在AD疾病进程中伴随着广泛的炎症反应,炎症反应与其他机制紧密联系,起到至关重要的作用。文中主要从小胶质细胞、星形胶质细胞、单核细胞、炎症介质等方面对目前AD神经炎症反应的研究进展进行综述。
Alzheimer's disease(AD) is the most common type of dementia. The cognitive and behavioral impairment seriously affects the health of the elderly. There are many doctrines about the mechanism of AD. More and more researches showed that the progression of AD is accompanied with extensive inflammatory response, inflammation is closely connected with other mechanisms and plays an important role in AD. The progress of inflammatory response in the aspects of microglia, astrocyte, monocyte and inflammation mediators was reviewed.
Alzheimer's disease(AD) is the most common type of dementia. The cognitive and behavioral impairment seriously affects the health of the elderly. There are many doctrines about the mechanism of AD. More and more researches showed that the progression of AD is accompanied with extensive inflammatory response, inflammation is closely connected with other mechanisms and plays an important role in AD. The progress of inflammatory response in the aspects of microglia, astrocyte, monocyte and inflammation mediators was reviewed.
引文
[1]Chan KY,Wang W,Wu JJ,et al.Epidemiology of Alzheimer's disease and other forms of dementia in China,1990-2010:a systematic review and analysis[J].Lancet,2013,381:2016-2023
[2]Zhang B,Gaiteri C,Bodea LG,et al.Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease[J].Cell,2013,153:707-720
[3]Mosher KI,Wyss-Coray T.Microglial dysfunction in brain aging and Alzheimer’s disease[J].Biochem Pharmacol,2014,88:594-604
[4]Salminen A,Ojala J,Kauppinen A,et al.Inflammation in Alzheimer’s disease:amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors[J].Prog Neurobiol,2009,87:181-194
[5]Solito E,Sastre M.Microglia function in Alzheimer's disease[J].Front Pharmacol,2012,3:14.
[6]Heneka MT,Kummer MP,Stutz A,et al.NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice[J].Nature,2013,493:674-678
[7]Hatami A,Albay R 3rd,Monjazeb S,et al.Monoclonal antibodies against Aβ42 fibrils distinguish multiple aggregation state polymorphisms in vitro and in Alzheimer disease brain[J].J Biol Chem,2014,289:32131-3243
[8]Grathwohl SA,K?lin RE,Bolmont T,et al.Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia[J].Nat Neurosci,2009,12:1361-1363
[9]Krabbe G,Halle A,Matyash V,et al.Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology[J].PLo S One,2013,8:e60921
[10]Maphis N,Xu G,Kokiko-Cochran ON,et al.Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain[J].Brain,2015,138:1738-1755
[11]Jimenez S,Baglietto-Vargas D,Caballero C,et al.Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease:age-dependent switch in the microglial phenotype from alternative to classic[J].J Neurosci,2008,28:11650-11661
[12]Schubert P,Rudolphi K.Interfering with the pathologic activation of microglial cells and astrocytes in dementia[J].Alzheimer Dis Assoc Disord,1998,12 Suppl 2:S21-28
[13]Lai W,Wu J,Zou X,et al.Secretome analyses of Aβ(1-42)stimulated hippocampal astrocytes reveal that CXCL10 is involved in astrocyte migration[J].J Proteome Res,2013,12:832-843
[14]Zhao J,O’Connor T,Vassar R.The contribution of activated astrocytes to Aβproduction:implications for Alzheimer’s disease pathogenesis[J].J Neuroinflammation,2011,8:150
[15]Rossner S,Lange-Dohna C,Zeitschel U,et al.Alzheimer’s diseaseβ-secretase BACE1 is not a neuron-specific enzyme[J].J Neurochem,2005,92:226-234
[16]Veeraraghavalu K,Zhang C,Zhang X,et al.Age-dependent,non-cellautonomous deposition of amyloid from synthesis ofβ-amyloid by cells other than excitatory neurons[J].J Neurosci,2014,34:3668-3673
[17]Beauquis J,Pavía P,Pomilio C,et al.Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice,model of Alzheimer’s disease[J].Exp Neurol,2013,239:28-37
[18]Padmanabhan J,Levy M,Dickson DW,et al.Alpha1-antichymotrypsin,an inflammatory protein overexpressed in Alzheimer’s disease brain,induces tau phosphorylation in neurons[J].Brain,2006,129:3020-3034
[19]林律,徐淑君,王钦文.星形胶质细胞介导的β淀粉样蛋白代谢与阿尔茨海默病早期的关系[J].生物化学与生物物理进展,2012,39:715-720
[20]Ziegler-Heitbrock L,Ancuta P,Crowe S,et al.Nomenclature of monocytes and dendritic cells in blood[J].Blood,2010,116:e74-e80
[21]Liu C,Cui G,Zhu M,et al.Neuroinflammation in Alzheimer’s disease:chemokines produced by astrocytes and chemokine receptors[J].Int JClin Exp Pathol,2014,7:8342-8355
[22]Bell RD,Zlokovic BV.Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease[J].Acta Neuropathol,2009,118:103-113
[23]Zlokovic BV.The blood-brain barrier in health and chronic neurodegenerative disorders[J].Neuron,2008,57:178-201
[24]El Khoury J,Toft M,Hickman SE,et al.Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease[J].Nat Med,2007,13:432-438
[25]Naert G,Rivest S.CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease[J].J Neurosci,2011,31:6208-6220
[26]Michaud JP,Bellavance MA,Préfontaine P,et al.Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta[J].Cell Rep,2013,5:646-653
[27]Koronyo Y,Salumbides BC,Sheyn J,et al.Therapeutic effects of glatiramer acetate and grafted CD115(+)monocytes in a mouse model of Alzheimer’s disease[J].Brain,2015,138:2399-2422
[28]Ginhoux F,Jung S.Monocytes and macrophages:developmental pathways and tissue homeostasis[J].Nat Rev Immunol,2014,14:392-404
[29]Fiala M,Lin J,Ringman J,et al.Ineffective phagocytosis of amyloidbeta by macrophages of Alzheimer's disease patients[J].J Alzheimers Dis,2005,7:221-232
[30]Sheng JG,Zhu SG,Jones RA,et al.Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo[J].Exp Neurol,2000,163:388-391
[31]Pang Y,Tien LT,Zhu H,et al.Interleukin-1 receptor antagonist reduces neonatal lipopolysaccharide-induced long-lasting neurobehavioral deficits and dopaminergic neuronal injury in adult rats[J].Int J Mol Sci,2015,16:8635-8654
[32]Kitazawa M,Cheng D,Tsukamoto MR,et al.Blocking IL-1 signaling rescues cognition,attenuates tau pathology,and restores neuronal beta-catenin pathway function in an Alzheimer’s disease model[J].JImmunol,2011,187:6539-6549
[33]Ji C,Song C,Aisa HA,et al.Gossypium herbaceam L.extracts ameliorate disequilibrium of IL-1RA/IL-1beta ratio to attenuate inflammatory process induced by amyloid beta in rats[J].Curr Alzheimer Res,2012,9:953-961
[34]Matousek SB,Ghosh S,Shaftel SS,et al.Chronic IL-1β-mediated neuroinflammation mitigates amyloid pathology in a mouse model of Alzheimer’s disease without inducing overt neurodegeneration[J].JNeuroimmune Pharmaco,2012,7:156-164
[35]Wright CB,Sacco RL,Rundek T,et al.Interleukin-6 is associated with cognitive function:the Northern Manhattan Study[J].J Stroke Cerebrovasc Dis,2006,15:34-38
[36]Su JH,Anderson AJ,Cribbs DH,et al.Fas and Fas ligand are associated with neuritic degeneration in the AD brain and participate in beta-amyloid-induced neuronal death[J].Neurobiol Dis,2003,12:182-193
[37]Ringheim GE,Szczepanik AM,Petko W,et al.Enhancement of betaamyloid precursor protein transcription and expression by the soluble interleukin-6 receptor/interleukin-6 complex[J].Brain Res Mol Brain Res,1998,55:35-44
[38]Herman AM,Khandelwal PJ,Rebeck GW,et al.Wild type TDP-43induces neuro-inflammation and alters APP metabolism in lentiviral gene transfer models[J].Exp Neurol,2012,235:297-305
[39]Orellana DI,Quintanilla RA,Gonzalez-Billault C,et al.Role of the JAKs/STATs pathway in the intracellular calcium changes induced by interleukin-6 in hippocampal neurons[J].Neurotox Res,2005,8:295-304
[40]Hryniewicz A,Bialuk I,Kaminski KA,et al.Impairment of recognition memory in interleukin-6 knock-out mice[J].Eur JPharmacol,2007,577:219-220
[41]蔡志友,晏勇,晏宁,等.阿尔茨海默病患者血清中血管内皮生长因子和炎症因子相关性研究[J].中国老年学杂志,2008,28:998-999
[42]Bhaskar K,Maphis N,Xu G,et al.Microglial derived tumor necrosis factor-alpha drives Alzheimer’s disease-related neuronal cell cycle events[J].Neurobiol Dis,2014,62:273-285
[43]Wong D,Prameya R,Dorovini-Zis K.In vitro adhesion and migration of T lymphocytes across monolayers of human brain microvessel endothelial cells:regulation by ICAM-1,VCAM-1,E-selectin and PECAM-1[J].J Neuropathol Exp Neurol,1999,58:138-152
[44]Tobinick E,Gross H,Weinberger A,et al.TNF-alpha modulation for treatment of Alzheimer's disease:a 6-month pilot study[J].Med Gen Med,2006,8:25
[45]Shimizu E,Kawahara K,Kajizono M,et al.IL-4-induced selective clearance of oligomericβ-amyloid pepetide(1-42)by rat primary type2microglia[J].J Immunol,2008,181:6503-6513
[46]Chakrabarty P,Tianbai L,Herring A,et al.Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition[J].Mol Neurodegener,2012,7:36
[47]Latta CH,Sudduth TL,Weekman EM,et al.Determining the role of IL-4 induced neuroinflammation in microglial activity and amyloid-βusing BV2 microglial cells and APP/PS1 transgenic mice[J].JNeuroinflammation,2015,12:41
[48]李冰,张军,吴蓓,等.IL-10对Aβ1-42诱导的阿尔茨海默病模型大鼠的保护作用[J].江苏医药,2012,38:2116-2118
[49]Guillot-Sestier MV,Doty KR,Gate D,et al.IL10deficiency rebalances innate immunity to mitigate Alzheimer-like Pathology[J].Neuron,2015,85:534-548
[50]Walport MJ.Complement.Second of two parts[J].N Engl J Med,2001,344:1140-1144
[51]Eikelenboom P,Veerhuis R.The role of complement and activatd microglia in the pathogenesis of Alzheimer’s disease[J].Neurobiol Aging,1996,17:673-680
[52]Lian H,Litvinchuk A,Chiang AC,et al.Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer’s Disease[J].J Neurosci,2016,36:577-589
[53]Landlinger C,Oberleitner L,Gruber P,et al.Active immunization against complement factor C5a:a new therapeutic approach for Alzheimer’s disease[J].J Neuroinflammation,2015,12:150
[54]Marcel M,Peng Y,Jiang L,et al.Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegenerationand modulation of the microglia/macrophage phenotype in amyloidprecursor protein transgenic mice[J].JNeurosci,2008,28:6333-6341
[55]Latta CH,Brothers HM,Wilcock DM.Neuroinflammationin Alzheimer’s disease;A source of heterogeneity and target for personalized therapy[J].Neuroscience,2015,302:103-111
[2]Zhang B,Gaiteri C,Bodea LG,et al.Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease[J].Cell,2013,153:707-720
[3]Mosher KI,Wyss-Coray T.Microglial dysfunction in brain aging and Alzheimer’s disease[J].Biochem Pharmacol,2014,88:594-604
[4]Salminen A,Ojala J,Kauppinen A,et al.Inflammation in Alzheimer’s disease:amyloid-beta oligomers trigger innate immunity defence via pattern recognition receptors[J].Prog Neurobiol,2009,87:181-194
[5]Solito E,Sastre M.Microglia function in Alzheimer's disease[J].Front Pharmacol,2012,3:14.
[6]Heneka MT,Kummer MP,Stutz A,et al.NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice[J].Nature,2013,493:674-678
[7]Hatami A,Albay R 3rd,Monjazeb S,et al.Monoclonal antibodies against Aβ42 fibrils distinguish multiple aggregation state polymorphisms in vitro and in Alzheimer disease brain[J].J Biol Chem,2014,289:32131-3243
[8]Grathwohl SA,K?lin RE,Bolmont T,et al.Formation and maintenance of Alzheimer’s disease beta-amyloid plaques in the absence of microglia[J].Nat Neurosci,2009,12:1361-1363
[9]Krabbe G,Halle A,Matyash V,et al.Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology[J].PLo S One,2013,8:e60921
[10]Maphis N,Xu G,Kokiko-Cochran ON,et al.Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain[J].Brain,2015,138:1738-1755
[11]Jimenez S,Baglietto-Vargas D,Caballero C,et al.Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease:age-dependent switch in the microglial phenotype from alternative to classic[J].J Neurosci,2008,28:11650-11661
[12]Schubert P,Rudolphi K.Interfering with the pathologic activation of microglial cells and astrocytes in dementia[J].Alzheimer Dis Assoc Disord,1998,12 Suppl 2:S21-28
[13]Lai W,Wu J,Zou X,et al.Secretome analyses of Aβ(1-42)stimulated hippocampal astrocytes reveal that CXCL10 is involved in astrocyte migration[J].J Proteome Res,2013,12:832-843
[14]Zhao J,O’Connor T,Vassar R.The contribution of activated astrocytes to Aβproduction:implications for Alzheimer’s disease pathogenesis[J].J Neuroinflammation,2011,8:150
[15]Rossner S,Lange-Dohna C,Zeitschel U,et al.Alzheimer’s diseaseβ-secretase BACE1 is not a neuron-specific enzyme[J].J Neurochem,2005,92:226-234
[16]Veeraraghavalu K,Zhang C,Zhang X,et al.Age-dependent,non-cellautonomous deposition of amyloid from synthesis ofβ-amyloid by cells other than excitatory neurons[J].J Neurosci,2014,34:3668-3673
[17]Beauquis J,Pavía P,Pomilio C,et al.Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice,model of Alzheimer’s disease[J].Exp Neurol,2013,239:28-37
[18]Padmanabhan J,Levy M,Dickson DW,et al.Alpha1-antichymotrypsin,an inflammatory protein overexpressed in Alzheimer’s disease brain,induces tau phosphorylation in neurons[J].Brain,2006,129:3020-3034
[19]林律,徐淑君,王钦文.星形胶质细胞介导的β淀粉样蛋白代谢与阿尔茨海默病早期的关系[J].生物化学与生物物理进展,2012,39:715-720
[20]Ziegler-Heitbrock L,Ancuta P,Crowe S,et al.Nomenclature of monocytes and dendritic cells in blood[J].Blood,2010,116:e74-e80
[21]Liu C,Cui G,Zhu M,et al.Neuroinflammation in Alzheimer’s disease:chemokines produced by astrocytes and chemokine receptors[J].Int JClin Exp Pathol,2014,7:8342-8355
[22]Bell RD,Zlokovic BV.Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease[J].Acta Neuropathol,2009,118:103-113
[23]Zlokovic BV.The blood-brain barrier in health and chronic neurodegenerative disorders[J].Neuron,2008,57:178-201
[24]El Khoury J,Toft M,Hickman SE,et al.Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease[J].Nat Med,2007,13:432-438
[25]Naert G,Rivest S.CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease[J].J Neurosci,2011,31:6208-6220
[26]Michaud JP,Bellavance MA,Préfontaine P,et al.Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta[J].Cell Rep,2013,5:646-653
[27]Koronyo Y,Salumbides BC,Sheyn J,et al.Therapeutic effects of glatiramer acetate and grafted CD115(+)monocytes in a mouse model of Alzheimer’s disease[J].Brain,2015,138:2399-2422
[28]Ginhoux F,Jung S.Monocytes and macrophages:developmental pathways and tissue homeostasis[J].Nat Rev Immunol,2014,14:392-404
[29]Fiala M,Lin J,Ringman J,et al.Ineffective phagocytosis of amyloidbeta by macrophages of Alzheimer's disease patients[J].J Alzheimers Dis,2005,7:221-232
[30]Sheng JG,Zhu SG,Jones RA,et al.Interleukin-1 promotes expression and phosphorylation of neurofilament and tau proteins in vivo[J].Exp Neurol,2000,163:388-391
[31]Pang Y,Tien LT,Zhu H,et al.Interleukin-1 receptor antagonist reduces neonatal lipopolysaccharide-induced long-lasting neurobehavioral deficits and dopaminergic neuronal injury in adult rats[J].Int J Mol Sci,2015,16:8635-8654
[32]Kitazawa M,Cheng D,Tsukamoto MR,et al.Blocking IL-1 signaling rescues cognition,attenuates tau pathology,and restores neuronal beta-catenin pathway function in an Alzheimer’s disease model[J].JImmunol,2011,187:6539-6549
[33]Ji C,Song C,Aisa HA,et al.Gossypium herbaceam L.extracts ameliorate disequilibrium of IL-1RA/IL-1beta ratio to attenuate inflammatory process induced by amyloid beta in rats[J].Curr Alzheimer Res,2012,9:953-961
[34]Matousek SB,Ghosh S,Shaftel SS,et al.Chronic IL-1β-mediated neuroinflammation mitigates amyloid pathology in a mouse model of Alzheimer’s disease without inducing overt neurodegeneration[J].JNeuroimmune Pharmaco,2012,7:156-164
[35]Wright CB,Sacco RL,Rundek T,et al.Interleukin-6 is associated with cognitive function:the Northern Manhattan Study[J].J Stroke Cerebrovasc Dis,2006,15:34-38
[36]Su JH,Anderson AJ,Cribbs DH,et al.Fas and Fas ligand are associated with neuritic degeneration in the AD brain and participate in beta-amyloid-induced neuronal death[J].Neurobiol Dis,2003,12:182-193
[37]Ringheim GE,Szczepanik AM,Petko W,et al.Enhancement of betaamyloid precursor protein transcription and expression by the soluble interleukin-6 receptor/interleukin-6 complex[J].Brain Res Mol Brain Res,1998,55:35-44
[38]Herman AM,Khandelwal PJ,Rebeck GW,et al.Wild type TDP-43induces neuro-inflammation and alters APP metabolism in lentiviral gene transfer models[J].Exp Neurol,2012,235:297-305
[39]Orellana DI,Quintanilla RA,Gonzalez-Billault C,et al.Role of the JAKs/STATs pathway in the intracellular calcium changes induced by interleukin-6 in hippocampal neurons[J].Neurotox Res,2005,8:295-304
[40]Hryniewicz A,Bialuk I,Kaminski KA,et al.Impairment of recognition memory in interleukin-6 knock-out mice[J].Eur JPharmacol,2007,577:219-220
[41]蔡志友,晏勇,晏宁,等.阿尔茨海默病患者血清中血管内皮生长因子和炎症因子相关性研究[J].中国老年学杂志,2008,28:998-999
[42]Bhaskar K,Maphis N,Xu G,et al.Microglial derived tumor necrosis factor-alpha drives Alzheimer’s disease-related neuronal cell cycle events[J].Neurobiol Dis,2014,62:273-285
[43]Wong D,Prameya R,Dorovini-Zis K.In vitro adhesion and migration of T lymphocytes across monolayers of human brain microvessel endothelial cells:regulation by ICAM-1,VCAM-1,E-selectin and PECAM-1[J].J Neuropathol Exp Neurol,1999,58:138-152
[44]Tobinick E,Gross H,Weinberger A,et al.TNF-alpha modulation for treatment of Alzheimer's disease:a 6-month pilot study[J].Med Gen Med,2006,8:25
[45]Shimizu E,Kawahara K,Kajizono M,et al.IL-4-induced selective clearance of oligomericβ-amyloid pepetide(1-42)by rat primary type2microglia[J].J Immunol,2008,181:6503-6513
[46]Chakrabarty P,Tianbai L,Herring A,et al.Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition[J].Mol Neurodegener,2012,7:36
[47]Latta CH,Sudduth TL,Weekman EM,et al.Determining the role of IL-4 induced neuroinflammation in microglial activity and amyloid-βusing BV2 microglial cells and APP/PS1 transgenic mice[J].JNeuroinflammation,2015,12:41
[48]李冰,张军,吴蓓,等.IL-10对Aβ1-42诱导的阿尔茨海默病模型大鼠的保护作用[J].江苏医药,2012,38:2116-2118
[49]Guillot-Sestier MV,Doty KR,Gate D,et al.IL10deficiency rebalances innate immunity to mitigate Alzheimer-like Pathology[J].Neuron,2015,85:534-548
[50]Walport MJ.Complement.Second of two parts[J].N Engl J Med,2001,344:1140-1144
[51]Eikelenboom P,Veerhuis R.The role of complement and activatd microglia in the pathogenesis of Alzheimer’s disease[J].Neurobiol Aging,1996,17:673-680
[52]Lian H,Litvinchuk A,Chiang AC,et al.Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer’s Disease[J].J Neurosci,2016,36:577-589
[53]Landlinger C,Oberleitner L,Gruber P,et al.Active immunization against complement factor C5a:a new therapeutic approach for Alzheimer’s disease[J].J Neuroinflammation,2015,12:150
[54]Marcel M,Peng Y,Jiang L,et al.Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegenerationand modulation of the microglia/macrophage phenotype in amyloidprecursor protein transgenic mice[J].JNeurosci,2008,28:6333-6341
[55]Latta CH,Brothers HM,Wilcock DM.Neuroinflammationin Alzheimer’s disease;A source of heterogeneity and target for personalized therapy[J].Neuroscience,2015,302:103-111