Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease
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摘要
The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.
The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.
The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.
引文
Abood WN,Fahmi I,Abdulla MA,Ismail S(2014)Immunomodulatory effect of an isolated fraction from Tinospora crispa on intracellular expression of INF-γ,IL-6 and IL-8.BMC Complement Altern Med 14:205.
Abraham M,Karni A,Dembinsky A,Miller A,Gandhi R,Anderson D,Weiner HL(2008)In vitro induction of regulatory T cells by anti-CD3 antibody in humans.J Autoimmun 30:21-28.
Baek H,Ye M,Kang GH,Lee C,Lee G,Choi DB,Jung J,Kim H,Lee S,Kim JS,Lee HJ,Shim I,Lee JH,Bae H(2016)Neuroprotective effects of CD4+CD25+Foxp3+regulatory T cells in a 3xTg-AD Alzheimer’s disease model.Oncotarget 7:69347-69357.
Bali J,Gheinani HA,Zurbriggen S,Rajendran L(2012)Role of genes linked to sporadic Alzheimer’s disease risk in the production ofβ-amyloid peptides.Proc Nat Acad Sci U S A 109:15307-15311.
Bassani TB,Turnes JM,Moura EL,Bonato JM,Cóppola-Segovia V,Zanata SM,Oliveira RM,Vital MA(2017)Effects of curcumin on short-term spatial and recognition memory,adult neurogenesis and neuroinflammation in a streptozotocin-induced model of dementia of Alzheimer’s type.Behav Brain Res335:41-54.
Bassil N,Grossberg GT(2009)Novel regimens and delivery systems in the pharmacological treatnent of Alzheimer’s disease.Drugs 23:293-307.
Blockx I,Einstein S,Guns PJ,Van Audekerke J,Guglielmetti C,Zago W,Roose D,Verhoye M,Van der Linden A,Bard F(2016)Monitoring blood-brain barrier integrity following amyloid-βimmunotherapy using gadolinium-enhanced MRIin a PDAPP mouse model.J Alzheimers Dis 54:723-735.
Borchelt DR(2018)B6.Cg-Tg(APP695)3Dbo Tg(PSEN1dE9)S9Dbo/Mmjax.https://www.jax.org/strain/005866.Accessed August 5,2018.
Borre Y,Bosman E,Lemstra S,Westphal KG,Olivier B,Oosting RS(2012)Memantine partly rescues behavioral and cognitive deficits in an animal model of neurodegeneration.Neuropharmacology 62:2010-2017.
Borre YE,Panagaki T,Koelink PJ,Morgan ME,Hendriksen H,Garssen J,Kraneveld AD,Olivier B,Oosting RS(2014)Neuroprotective and cognitive enhancing effects of a multi-targeted food intervention in an animal model of neurodegeneration and depression.Neuropharmacology 79:738-749.
Burns A,Iliffe S(2009)Alzheimer’s disease.BMJ 338:b158.
Cao W,Zheng H(2018)Peripheral immune system in aging and Alzheimer’s disease.Mol Neurodegener 13:51.
Carvajal FJ,Mattison HA,Cerpa W(2016)Role of NMDA-mediated glutamatergic signaling in chronic and acute neuropathologies.Neural Plasticity 2016:2701526.
Casas-Grajales S,Vázquez-Flores LF,Ramos-Tovar E,Hernández-Aquino E,Flores-Beltrán RE,Cerda-García-Rojas CM,Camacho J,Shibayama M,Tsutsumi V,Muriel P(2017)Quercetin reverses experimental cirrhosis by immunomodulation of the proinflammatory and profibrotic processes.Fundam Clin Pharmacol 31:610-624.
Chen J,Li S,Sun W,Li J(2015)Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activity.PLoS One 10:e0123864.
Chen YT,Nikulina K,Lazarev S,Bahrami AF,Noble LB,Gallup M,McNamara NA(2010)Interleukin-1 as a phenotypic immunomodulator in keratinizing squamous metaplasia of the ocular surface in Sjogren’s syndrome.Am J Pathol177:1333-1343.
Cheng D,Spiro AS,Jenner AM,Garner B,Karl T(2014)Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice.J Alzheimers Dis 42:1383-1396.
Cheng XR,Zhou WX,Zhang YX(2014)The behavioral,pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an Alzheimer’s disease animal model.Ageing Res Rev 13:13-37.
Cherry JD,Olschowka JA,O’Banion MK(2014)Neuroinflammation and M2 microglia:the good,the bad,and the inflamed.J Neuroinflammation 11:98.
Chung JA,Cummings JL(2000)Neurobehavioral and neuropsychiatric symptoms in Alzheimer’s disease:characteristics and treatment.Neurol Clin 18:829-846.
Damasceno FS,Barison MJ,Pral EM,Paes LS,Silber AM(2014)Memantine,an antagonist of the NMDA glutamate receptor,affects cell proliferation,differentiation and the intracellular cycle and induces apoptosis in Trypanosoma cruzi.PLo S Negl Trop Dis 8:e2717.
Do Carmo S,Cuello AC(2013)Modeling Alzheimer’s disease in transgenic rats.Mol Neurodegener 8:37.
Dorszewska J,Prendecki M,Oczkowska A,Dezor M,Kozubski W(2016)Molecular basis of familial and sporadic Alzheimer’s disease.Curr Alzheimer Res13:952-963.
El-Sisi AE,Sokar SS,Salem TA,Abu Risha SE(2015)PPARγ-dependent anti-tumor and immunomodulatory sctions of pioglitazone.J Immunotoxicol 12:308-316.
Fernandez PL,Britton GB,Rao KS(2013)Potential immunotargets for Alzheimer’s disease treatment strategies.J Alzheimers Dis 33:297-312.
Fischer R,Kontermann RE,Maier O(2015)Targeting sTNF/TNFR1 signaling as a new therapeutic strategy.Antibodies 4:48-70.
Fisher Y,Strominger I,Biton S,Nemirovsky A,Baron R,Monsonego A(2014)Th1polarization of T cells injected into the cerebrospinal fluid induces brain immunosurveillance.J Immunol 192:92-102.
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 Pathol152:307-317.
Giannoulia-Karantana A,Vlachou A,Polychronopoulou S,Papassotiriou I,Chrousos GP(2006)Melatonin and immunomodulation:connections and potential clinical applications.Neuroimmunomodulation 13:133-144.
Glass CK,Saijo K,Winner B,Marchetto MC,Gage FH(2010)Mechanisms underlying inflammation in neurodegeneration.Cell 140,918-934.
Granowitz EV,Porat R,Mier JW,Pribble JP,Stiles DM,Bloedow DC,Catalano MA,Wolff SM,Dinarello CA(1992)Pharmacokinetics,safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans.Cytokine 4:353-360.
Guerreiro R,Bras J(2015)The age factor in Alzheimer’s disease.Genome Med7:106.
Hardy JA,Higgins GA(1992)Alzheimer’s disease:the amyloid cascade hypothesis.Science 256:184-185.
Hartman RE,Ross DM(2018)Effects and mechanisms of actions of phytochemicals on Alzheimer’s disease neuropathology.Front Biosci(Elite Ed)10:300-333.
Heneka MT,Carson MJ,El Khoury J,Landreth GE,Brosseron F,Feinstein DL,Jacobs AH,Wyss-Coray T,Vitorica J,Ransohoff RM,Herrup K,Frautschy SA,Finsen B,Brown GC,Verkhratsky A,Yamanaka K,Koistinaho J,Latz E,Halle A,Petzold GC,et al.(2015)Neuroinflammation in Alzheimer’s disease.Lancet Neurol 14:388-405.
Hirahashi J,Kawahata K,Arita M,Iwamoto R,Hishikawa K,Honda M,Hamasaki Y,Tanaka M,Okubo K,Kurosawa M,Takase O,Nakakuki M,Saiga K,Suzuki K,Kawachi S,Tojo A,Seki G,Marumo T,Hayashi M,Fujita T(2014)Immunomodulation with eicosapentaenoic acid supports the treatment of autoimmune small-vessel vasculitis.Sci Rep 4:6406.
Hjorth E,Freund-Levi Y(2012)Immunomodulation of microglia by docosahexaenoic acid and eicosapentaenoic acid.Curr Opin Clin Nutr Metab Care 15:134-143.
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 4:97-100.
Hosokawa M,Kasai R,Higuchi K,Takeshita S,Shimizu K,Hamamoto H,Honma A,Irino M,Toda K,Matsumura A,et al.(1984)Grading score system:a method for evaluation of the degree of senescence in senescence accelerated mouse(SAM).Mech Ageing Dev 26:91-102.
Hu N,Yu JT,Tan L,Wang YL,Sun L,Tan L(2013)Nutrition and the risk of Alzheimer’s disease.Biomed Res Int 2013:524820.
Hughes TF,Andel R,Small BJ,Borenstein AR,Mortimer JA,Wolk A,Johansson B,Fratiglioni L,Pedersen NL,Gatz M(2010)Midlife fruit and vegetable consumption and risk of dementia in later life in Swedish twins.Am J Geriat Psychiatry 18:413-420.
Insausti CL,Blanquer M,García-Hernández AM,Castellanos G,Moraleda JM(2014)Amniotic membrane-derived stem cells:immunomodulatory properties and potential clinical application.Stem Cells Cloning 7:53-63.
Iwami D,Nonomura K,Shirasugi N,Niimi M(2011)Immunomodulatory effects of eicosapentaenoic acid through induction of regulatory T cells.Int Immunopharmacol 11:384-389.
Jiang C,Ting AT,Seed B(1998)PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.Nature 391:82-86.
Joo IL,Lai AY,Bazzigaluppi P,Koletar MM,Dorr A,Brown ME,Thomason LA,Sled JG,McLaurin J,Stefanovic B(2017)Early neurovascular dysfunction in a transgenic rat model of Alzheimer’s disease.Sci Rep 7:46427.
Kidd BA,Wroblewska A,Boland MR,Agudo J,Merad M,Tatonetti NP,Brown BD,Dudley JT(2016)Mapping the effects of drugs on the immune system.Nat Biotechnol 34:47-54.
Kim KS,Kim HS,Park JM,Kim HW,Park MK,Lee HS,Lim DS,Lee TH,Chopp M,Moon J(2013)Long-term immunomodulatory effect of amniotic stem cells in an Alzheimer’s disease model.Neurobiol Aging 34:2408-2420.
Koch C,Brovkina L,Ruehl R,Worm M(2006)Immunomodulation by dietary n3-polyunsaturated acids(PUFA)in vitro.J Allergy Clin Immunol 117:S147.
Lambracht-Washington D,Rosenberg RN(2015)A noninflammatory immune response in aged DNA Aβ42-immunized mice supports its safety for possible immunotherapy in AD patients.Neurobiol Aging 36:1274-1281.
Lee HJ,Lee JK,Lee H,Carter JE,Chang JW,Oh W,Yang YS,Suh JG,Lee BH,Jin HK,Bae JS(2012)Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer’s disease mouse model through modulation of neuroinflammation.Neurobiol Aging33:588-602.
Lee SY,Chen SL,Chang YH,Chen PS,Huang SY,Tzeng NS,Wang LJ,Lee IH,Wang TY,Chen KC,Yang YK,Hong JS,Lu RB(2015)Low-dose memantine attenuated methadone dose in opioid-dependent patients:a 12-week double-blind randomized controlled trial.Sci Rep 5:10140.
Li C,Ebrahimi A,Schluesener H(2013)Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer’s disease.Ageing Res Rev 12:116-140.
Li Q,Lebson L,Lee DC,Nash K,Grimm J,Rosenthal A,Selenica ML,Morgan D,Gordon MN(2012)Chronological age impacts immunotherapy and monocyte uptake independent of amyloid load.J Neuroimmune Pharmacol 7:202-214.
Li Y,Yao J,Han C,Yang J,Chaudhry MT,Wang S,Liu H,Yin Y(2016)Quercetin,inflammation and immunity.Nutrients 8:167.
Liao YF,Wang BJ,Cheng HT,Kuo LH,Wolfe MS(2004)Tumor necrosis factor-alpha,interleukin-1beta,and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein though a JNK-dependent MAPK pathway.J Biol Chem 279:49523-49532.
Libro R,Giacoppo S,Soundara Rajan T,Bramanti P,Mazzon E(2016)Natural phytochemicals in the treatment and prevention of dementia:An oveview.Molecules 21:518.
Liu CY,Guo SD,Yu JZ,Li YH,Zhang H,Feng L,Chai Z,Yuan HJ,Yang WF,Feng QJ,Xiao BG,Ma CG(2015)Fasudil mediates cell therapy of EAE by immunomodulating encephalomyelitic T cells and macrophages.Eur J Immunol 45:142-152.
Liu DS,Liu WJ,Chen L,Ou XM,Wang T,Feng YL,Zhang SF,Xu D,Chen YJ,Wen FQ(2009)Rosiglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates acrolein-induced airway mucus hypersecretion in rats.Toxicology 260:112-119.
Loi F,Cordova LA,Zhang R,Pajarinen J,Lin TH,Goodman SB,Yao Z(2016)The effects of immunomodulation by macrophage subsets on osteogenesis in vitro.Stem Cell Res Ther 7:15.
Lowinus T,Bose T,Busse S,Busse M,Reinhold D,Schraven B,Bommhardt UH(2016)Immunomodulation by memantine in therapy of Alzheimer’s disease is mediated through inhibition of Kv1.3 channels and T cell responsiveness.Oncotarget 7:53797-53807.
Luz-Crawford P,Kurte M,Bravo-Alegría J,Contreras R,Nova-Lamperti E,Tejedor G,No?l D,Jorgensen C,Figueroa F,Djouad F,Carrión F(2013)Mesenchymal stem cells generate a CD4+CD25+Foxp3+regulatory T cell population during the differentiation process of Th1 and Th17 cells.Stem Cell Res Ther 4:65.
Mac Pherson KP,Sompol P,Kannarkat GT,Chang J,Sniffen L,Wildner ME,Norris CM,Tansey MG(2017)Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles,decreases beta-amyloid plaque load,and rescues impaired long-term potentiation in 5xFAD mice.Neurobiol Dis 102:81-95.
Magatti M,Vertua E,Cagnoni A,Silini A,Parolini O(2018)The immunomodulatory properties of amniotic cells:The two sides of the coin.Cell Transplant27:31-44.
Mandrekar-Colucci S,Landreth GE(2010)Microglia and inflammation in Alzheimer’s disease.CNS Neurol Disord Drug Targets 9:156-167.
Mc Geer PL,McGeer EG(2013)The amyloid cascade-inflammatory hypothesis of Alzheimer disease:implications for therapy.Acta Neuropathol 126:479-497.
Mecha M,FeliúA,I?igo PM,Mestre L,Carrillo-Salinas FJ,Guaza C(2013)Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis:a role for A2A receptors.Neurobiol Dis 59:141-150.
Medrano-Campillo P,Sarmiento-Soto H,álvarez-Sánchez N,álvarez-Ríos AI,Guerrero JM,Rodríguez-Prieto I,Castillo-Palma MJ,Lardone PJ,Carrillo-Vico A(2015)Evaluation of the immunomodulatory effect of melatonin on the T-cell response in peripheral blood from systemic lupus erythematosus patients.J Pineal Res 58:219-226.
Mimica N,Presecki P(2009)Side effects of approved antidementives.Psychiatr Danub 21:108-113.
Naj AC,Jun G,Beecham GW,Wang LS,Vardarajan BN,Buros J,Gallins PJ,Buxbaum JD,Jarvik GP,Crane PK,Larson EB,Bird TD,Boeve BF,Graff-Radford NR,De Jager PL,Evans D,Schneider JA,Carrasquillo MM,Ertekin-Taner N,Younkin SG,et al.(2011)Common variants at MS4A4/MS4A6E,CD2AP,CD33 and EPHA1 are associated with late-onset Alzheimer‘s disease.Nat Genet43:436-441.
Nedumpun T,Wongyanin P,Sirisereewan C,Ritprajak P,Palaga T,Thanawongnuwech R,Suradhat S(2017)Interleukin-1 receptor antagonist:an early immunomodulatory cytokine induced by porcine reproductive and respiratory syndrome virus.J Gen Virol 98:77-88.
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 26:10129-10140.
Oddo S,Caccamo A,Kitazawa M,Tseng BP,LaFerla FM(2003)Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease.Neurobiol Aging 24:1063-1070.
Ohtaki H,Ylostalo JH,Foraker JE,Robinson AP,Reger RL,Shioda S,Prockop DJ(2008)Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses.Proc Natl Acad Sci U S A 105:14638-14643.
Onos KD,Sukoff Rizzo SJ,Howell GR,Sasner M(2016)Toward more predictive genetic mouse models of Alzheimer’s disease.Brain Res Bull 122:1-11.
Parsa R,Andresen P,Gillett A,Mia S,Zhang XM,Mayans S,Holmberg D,Harris RA(2012)Adoptive transfer of imunomodulatory M2 macrophages prevents type 1 diabetes in NOD mice.Diabetes 61:2881-2892.
Parrish WR,Gallowitsch Puerta M,Ochani M,Ochani K,Moskovic D,Lin X,Czura CJ,Miller EJ,Al-Abed Y,Tracey KJ,Pavlov VA(2006)Choline suppresses inflammatory responses.Shock 25:45.
Parrish WR,Rosas-Ballina M,Gallowitsch-Puerta M,Ochani M,Ochani K,Yang LH,Hudson L,Lin X,Patel N,Johnson SM,Chavan S,Goldstein RS,Czura CJ,Miller EJ,Al-Abed Y,Tracey KJ,Pavlov VA(2008)Modulation of TNF release requiresα7 subunit nicotinic acetylcholine receptor-mediated signaling.Mol Med 14:567-574.
Pavlov VA,Wang H,Czura CJ,Friedman SG,Tracey KJ(2003)The cholinergic anti-inflammatory pathway:a missing link in neuroimmunomodulation.Mol Med 9:125-134.
Petrasek T,Skurlova M,Maleninska K,Vojtechova I,Kristofikova Z,Matuskova H,Sirova J,Vales K,Ripova D,Stuchlik A(2016)A rat model of Alzheimer’s disease based on Abeta42 and pro-oxidative substances exhibits cognitive deficit and alterations in glutamatergic and cholinergic neurotransmitter systems.Front Aging Neurosci 8:83.
Riedel WJ(2014)Preventing cognitive decline in preclinical Alzheimer’s disease.Curr Opin Pharmacol 14:18-22.
Rivera-Escalera F,Matousek SB,Ghosh S,Olschowka JA,O’Banion MK(2014)Inteleukin-1βmediated amyloid plaque clearance is independent of CCR2signaling in the APP/PS1 mouse model of Alzheimer’s disease.Neurobiol Dis69:124-133.
Rodgers G,Doucette CD,Spurrell DR,Hoskin DW,West KA,Liwski RS(2009)Immunomodulatory effect of piperine on dendritic cell function(50.36).J Immunol 182:50.36.
Rodriquez-Santiago L,Alí-Torres J,Vidossich P,Sodupe M(2015)Coordination properties of a metal chelator clioquinol to Zn(2+)studied by static DFT and ab initio molecular dynamics.Phys Chem Chem Phys 17:13582-13589.
Rosset MB,Lui G,Dansokho C,Chaigneau T,Dorothée G(2015)Vaccine-induced Aβ-specific CD8+T cells do not trigger autoimune neuroinflammation in a murine model of Alzheimer’s disease.J Neuroinflammation 12:95.
Rosshart SP,Vassallo BG,Angeletti D,Hutchinson DS,Morgan AP,Takeda K,Hickman HD,McCulloch JA,Badger JH,Ajami NJ,Trinchieri G,Pardo-Manuel de Villena F,Yewdell JW,Rehermann B(2017)Wild mouse gut microbiota promotes host fitness and improves disease resistance.Cell 171:1015-1028.
Rowley TJ,McKinstry A,Greenidge E,Smith W,Flood P(2010)Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain.Br J Anaesth 105:201-207.
Sabogal-Guaqueta AM,Mu?oz-Manco JI,Ramírez-Pineda JR,Lamprea-Rodriguez M,Osorio E,Cardona-Gómez GP(2015)The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice.Neuropharmacology 93:134-145.
Saederup N,Cardona AE,Croft K,Mizutani M,Cotleur AC,Tsou CL,Ransohoff RM,Charo IF(2010)Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice.PLoS One5:e13693.
Sastre M,Walter J,Gentleman SM(2008)Interactions between APP secretases and inflammatory mediators.J Neuroinflammation 5:25.
Selkoe DJ(1991)The molecular pathology of Alzheimer’s disease.Neuron 6:487-498.
Serghides L,Patel SN,Ayi K,Lu Z,Gowda DC,Liles WC,Kain KC(2009)Rosiglitazone modulates the innate immune response to Plasmodium falciparum infection and improves outcome in experimental cerebral malaria.J Infect Dis199:1536-1545.
Sheng JG,Mrak RE,Griffin WS(1997)Neuritic plaque evolution in Alzheimer’s disease is accompanied by transition of activated microglia from primed to enlarged to phagocytic forms.Acta Neuropathol 94:1-5.
Shi M,Liu ZW,Wang FS(2011)Inmmunomodulatory properties and therapeutic application of mesenchymal stem cells.Clin Exp Immunol 164:1-8.
Shimada A,Hasegawa-Ishii S(2011)Senescence-accelerated Mice(SAMs)as a Model for Brain Aging and Immunosenescence.Aging Dis 2:414-435.
Singh S,Loke YK,Furberg CD(2011)Long-term use of thiazolidenediones and the associated risk of pneumonia or lower respiratory tract infection:systematic review and meta-analysis.Thorax 66:383-388.
Sinha AK,Bagchi AK(2004)Role of anti-CD3 in modulation of Th1-type immune response in Shigella dysenteriae infection.J Med Microbiol 53:1075-1081.
Song C,Zhang XY,Manku M(2009)Increased phospholipase A2 activity and inflammatory response but decreased nerve growth factor expression in the olfactory bulbectomized rat model of depression:effects of chronic ethyl-eicosapentaenoate treatment.J Neurosci 29:14-22.
Song Y,Chen X,Wang LY,Gao W,Zhu MJ(2013)Rho kinase inhibitor fasudil protects againstβ-amyloid-induced hippocampal neurodegeneration in rats.CNS Neurosci Ther 19:603-610.
Spires-Jones TL,Hyman BT(2014)The intersection of amyloid beta and tau synapses in Alzheimer’s disease.Neuron 82:756-771.
Sundaram JR,Poore CP,Sulaimee NHB,Pareek T,Cheong WF,Wenk MR,Pant HC,Frautschy SA,Low CM,Kesavapany S(2017)Curcumin ameliorates neuroinflammation,neurodegeneration,and memory deficits in p25 transgenic mousae model that bears hallmarks of Alzheimer’s disease.J Alzheimers Dis60:1429-1442.
Sunila ES,Kuttan G(2004)Immunomodulatory and antitumor activity of Piper longum Linn.and piperine.J Ethnopharmacol 90:339-346.
Thorlacius K,Slotta JE,Laschke MW,Wang Y,Menger MD,Jeppsson B,Thorlacius H(2006)Protective effect of fasudil,a Rho-kinase inhibitor,on chemokine expression,leukocyte recruitment,and hepatocellular apoptosis in septic liver injury.J Leukoc Biol 79:923-931.
Tong L,Prieto GA,Kramár EA,Smith ED,Cribbs DH,Lynch G,Cotman CW(2012)Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1βvia p38 mitogen-activated protein kinase.J Neurosci32:17714-17724.
Wang J,Lei X,Cheng XR,Zhang XR,Liu G,Cheng JP,Xu YR,Zeng J,Zhou WX,Zhang YX(2016)LW-AFC,a new formula derived from Liuwei Dihuang decoction,ameliorates behavioral and pathological deterioration via modulating the neuroendocrine-immune system in PrP-hAβPPswe/PS1ΔE9 transgenic mice..Alzheimer’s Res Ther 8:57.
Wang J,Zhang X,Cheng X,Cheng J,Liu F,Xu Y,Zeng J,Qiao S,Zhou W,Zhang Y(2017)LW-AFC,a new formula derived from Liuwei Dihuang decoction,ameliorates cognitive deterioration and modulates neuroendocrine-immune system in SAMP8 mouse.Curr Alzheimer Res 14:221-238.
Watkins LR,Milligan ED,Maier SF(2001)Glial activation:a driving force for pathological pain.Trends Neurosci 24:450-455.
Wisniewski T,Goni F(2014)Immunotherapy for Alzheimer’s disease.Biochem Pharmacol 88:499-507.
Yang Y,Cudaback E,Jorstad NL,Hemingway JF,Hagan CE,Melief EJ,Li X,Yoo T,Khademi SB,Montine KS,Montine TJ,Keene CD(2013)APOE3,but not APOE4,bone marrow transplantation mitigates behavioral and pathological changes in a mouse model of Alzheimer disease.Am J Pathol 183:905-917.
Yehuda S,Rabinovitz S(2014)Olfactory bulbectomy as a putative model for Alzheimer’:the protective role of essential fatty acids.PharmaNutrition 2:12-18.
Yu JZ,Li YH,Liu CY,Wang Q,Gu QF,Wang HQ,Zhang GX,Xiao BG,Ma CG(2017)Multitarget therapeutic effect of fasudil in APP/PS1 transgenic mice.CNS Neurological Disorders-Drug Targets 16:199-209.
Yu Y,Li X,Blanchard J,Li Y,Iqbal K,Liu F,Gong CX(2016)Insulin sensitizers improve learning and attenuate tau hyperphosphorylation and neuroinflammation in 3xTg-AD mice.J Neural Transm 122:593-606.
Zgair A,Lee JB,Wong JCM,Taha DA,Aram J,Di Virgilio D,McArthur JW,Cheng YK,Hennig IM,Barrett DA,Fischer PM,Constantinescu CS,Gershkovich P(2017)Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation.Sci Rep 7:14542.
Zhang YH,Raymick J,Sarkar S,Lahiri DK,Ray B,Holtzman D,Dumas M,Schmued LC(2013)Efficacy and toxicity of clioquinol treatment and A-beta42inoculation in the APP/PS1 mouse model of Alzheimer’s disease.Curr Alzheimer Res 10:494-506.
Zheng YZ,Deng G,Liang Q,Chen DF,Guo R,Lai RC(2017)Antioxidant activity of quercetin and its glucosides from propolis:A theoretical study.Sci Rep 7:7543.
Zhu D,Yang N,Liu YY,Zheng J,Ji C,Zuo PP(2016)M2 macrophage transplantation ameliorates cognitive dysfunction in amyloid-β-treated rats through regulation of microglial polarization.J Alzheimers Dis 52:483-495.
Zou C,Montagna E,Shi Y,Peters F,Blazquez-Llorca L,Shi S,Filser S,Dorostkar MM,Herms J(2015)Intraneuronal APP and extracellular Aβindependently cause dendritic spine pathology in transgenic mouse models of Alzheimer’s disease.Acta Neuropathol 129:909-920.
Zou C,Shi Y,Ohli J,Schüller U,Dorostkar MM,Herms J(2016)Neuroinflammation impairs adaptive structural plasticity of dendritic spines in a preclinical model of Alzheimer’s disease.Acta Neuropathol 131:235-246.
Abraham M,Karni A,Dembinsky A,Miller A,Gandhi R,Anderson D,Weiner HL(2008)In vitro induction of regulatory T cells by anti-CD3 antibody in humans.J Autoimmun 30:21-28.
Baek H,Ye M,Kang GH,Lee C,Lee G,Choi DB,Jung J,Kim H,Lee S,Kim JS,Lee HJ,Shim I,Lee JH,Bae H(2016)Neuroprotective effects of CD4+CD25+Foxp3+regulatory T cells in a 3xTg-AD Alzheimer’s disease model.Oncotarget 7:69347-69357.
Bali J,Gheinani HA,Zurbriggen S,Rajendran L(2012)Role of genes linked to sporadic Alzheimer’s disease risk in the production ofβ-amyloid peptides.Proc Nat Acad Sci U S A 109:15307-15311.
Bassani TB,Turnes JM,Moura EL,Bonato JM,Cóppola-Segovia V,Zanata SM,Oliveira RM,Vital MA(2017)Effects of curcumin on short-term spatial and recognition memory,adult neurogenesis and neuroinflammation in a streptozotocin-induced model of dementia of Alzheimer’s type.Behav Brain Res335:41-54.
Bassil N,Grossberg GT(2009)Novel regimens and delivery systems in the pharmacological treatnent of Alzheimer’s disease.Drugs 23:293-307.
Blockx I,Einstein S,Guns PJ,Van Audekerke J,Guglielmetti C,Zago W,Roose D,Verhoye M,Van der Linden A,Bard F(2016)Monitoring blood-brain barrier integrity following amyloid-βimmunotherapy using gadolinium-enhanced MRIin a PDAPP mouse model.J Alzheimers Dis 54:723-735.
Borchelt DR(2018)B6.Cg-Tg(APP695)3Dbo Tg(PSEN1dE9)S9Dbo/Mmjax.https://www.jax.org/strain/005866.Accessed August 5,2018.
Borre Y,Bosman E,Lemstra S,Westphal KG,Olivier B,Oosting RS(2012)Memantine partly rescues behavioral and cognitive deficits in an animal model of neurodegeneration.Neuropharmacology 62:2010-2017.
Borre YE,Panagaki T,Koelink PJ,Morgan ME,Hendriksen H,Garssen J,Kraneveld AD,Olivier B,Oosting RS(2014)Neuroprotective and cognitive enhancing effects of a multi-targeted food intervention in an animal model of neurodegeneration and depression.Neuropharmacology 79:738-749.
Burns A,Iliffe S(2009)Alzheimer’s disease.BMJ 338:b158.
Cao W,Zheng H(2018)Peripheral immune system in aging and Alzheimer’s disease.Mol Neurodegener 13:51.
Carvajal FJ,Mattison HA,Cerpa W(2016)Role of NMDA-mediated glutamatergic signaling in chronic and acute neuropathologies.Neural Plasticity 2016:2701526.
Casas-Grajales S,Vázquez-Flores LF,Ramos-Tovar E,Hernández-Aquino E,Flores-Beltrán RE,Cerda-García-Rojas CM,Camacho J,Shibayama M,Tsutsumi V,Muriel P(2017)Quercetin reverses experimental cirrhosis by immunomodulation of the proinflammatory and profibrotic processes.Fundam Clin Pharmacol 31:610-624.
Chen J,Li S,Sun W,Li J(2015)Anti-diabetes drug pioglitazone ameliorates synaptic defects in AD transgenic mice by inhibiting cyclin-dependent kinase5 activity.PLoS One 10:e0123864.
Chen YT,Nikulina K,Lazarev S,Bahrami AF,Noble LB,Gallup M,McNamara NA(2010)Interleukin-1 as a phenotypic immunomodulator in keratinizing squamous metaplasia of the ocular surface in Sjogren’s syndrome.Am J Pathol177:1333-1343.
Cheng D,Spiro AS,Jenner AM,Garner B,Karl T(2014)Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice.J Alzheimers Dis 42:1383-1396.
Cheng XR,Zhou WX,Zhang YX(2014)The behavioral,pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an Alzheimer’s disease animal model.Ageing Res Rev 13:13-37.
Cherry JD,Olschowka JA,O’Banion MK(2014)Neuroinflammation and M2 microglia:the good,the bad,and the inflamed.J Neuroinflammation 11:98.
Chung JA,Cummings JL(2000)Neurobehavioral and neuropsychiatric symptoms in Alzheimer’s disease:characteristics and treatment.Neurol Clin 18:829-846.
Damasceno FS,Barison MJ,Pral EM,Paes LS,Silber AM(2014)Memantine,an antagonist of the NMDA glutamate receptor,affects cell proliferation,differentiation and the intracellular cycle and induces apoptosis in Trypanosoma cruzi.PLo S Negl Trop Dis 8:e2717.
Do Carmo S,Cuello AC(2013)Modeling Alzheimer’s disease in transgenic rats.Mol Neurodegener 8:37.
Dorszewska J,Prendecki M,Oczkowska A,Dezor M,Kozubski W(2016)Molecular basis of familial and sporadic Alzheimer’s disease.Curr Alzheimer Res13:952-963.
El-Sisi AE,Sokar SS,Salem TA,Abu Risha SE(2015)PPARγ-dependent anti-tumor and immunomodulatory sctions of pioglitazone.J Immunotoxicol 12:308-316.
Fernandez PL,Britton GB,Rao KS(2013)Potential immunotargets for Alzheimer’s disease treatment strategies.J Alzheimers Dis 33:297-312.
Fischer R,Kontermann RE,Maier O(2015)Targeting sTNF/TNFR1 signaling as a new therapeutic strategy.Antibodies 4:48-70.
Fisher Y,Strominger I,Biton S,Nemirovsky A,Baron R,Monsonego A(2014)Th1polarization of T cells injected into the cerebrospinal fluid induces brain immunosurveillance.J Immunol 192:92-102.
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 Pathol152:307-317.
Giannoulia-Karantana A,Vlachou A,Polychronopoulou S,Papassotiriou I,Chrousos GP(2006)Melatonin and immunomodulation:connections and potential clinical applications.Neuroimmunomodulation 13:133-144.
Glass CK,Saijo K,Winner B,Marchetto MC,Gage FH(2010)Mechanisms underlying inflammation in neurodegeneration.Cell 140,918-934.
Granowitz EV,Porat R,Mier JW,Pribble JP,Stiles DM,Bloedow DC,Catalano MA,Wolff SM,Dinarello CA(1992)Pharmacokinetics,safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans.Cytokine 4:353-360.
Guerreiro R,Bras J(2015)The age factor in Alzheimer’s disease.Genome Med7:106.
Hardy JA,Higgins GA(1992)Alzheimer’s disease:the amyloid cascade hypothesis.Science 256:184-185.
Hartman RE,Ross DM(2018)Effects and mechanisms of actions of phytochemicals on Alzheimer’s disease neuropathology.Front Biosci(Elite Ed)10:300-333.
Heneka MT,Carson MJ,El Khoury J,Landreth GE,Brosseron F,Feinstein DL,Jacobs AH,Wyss-Coray T,Vitorica J,Ransohoff RM,Herrup K,Frautschy SA,Finsen B,Brown GC,Verkhratsky A,Yamanaka K,Koistinaho J,Latz E,Halle A,Petzold GC,et al.(2015)Neuroinflammation in Alzheimer’s disease.Lancet Neurol 14:388-405.
Hirahashi J,Kawahata K,Arita M,Iwamoto R,Hishikawa K,Honda M,Hamasaki Y,Tanaka M,Okubo K,Kurosawa M,Takase O,Nakakuki M,Saiga K,Suzuki K,Kawachi S,Tojo A,Seki G,Marumo T,Hayashi M,Fujita T(2014)Immunomodulation with eicosapentaenoic acid supports the treatment of autoimmune small-vessel vasculitis.Sci Rep 4:6406.
Hjorth E,Freund-Levi Y(2012)Immunomodulation of microglia by docosahexaenoic acid and eicosapentaenoic acid.Curr Opin Clin Nutr Metab Care 15:134-143.
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 4:97-100.
Hosokawa M,Kasai R,Higuchi K,Takeshita S,Shimizu K,Hamamoto H,Honma A,Irino M,Toda K,Matsumura A,et al.(1984)Grading score system:a method for evaluation of the degree of senescence in senescence accelerated mouse(SAM).Mech Ageing Dev 26:91-102.
Hu N,Yu JT,Tan L,Wang YL,Sun L,Tan L(2013)Nutrition and the risk of Alzheimer’s disease.Biomed Res Int 2013:524820.
Hughes TF,Andel R,Small BJ,Borenstein AR,Mortimer JA,Wolk A,Johansson B,Fratiglioni L,Pedersen NL,Gatz M(2010)Midlife fruit and vegetable consumption and risk of dementia in later life in Swedish twins.Am J Geriat Psychiatry 18:413-420.
Insausti CL,Blanquer M,García-Hernández AM,Castellanos G,Moraleda JM(2014)Amniotic membrane-derived stem cells:immunomodulatory properties and potential clinical application.Stem Cells Cloning 7:53-63.
Iwami D,Nonomura K,Shirasugi N,Niimi M(2011)Immunomodulatory effects of eicosapentaenoic acid through induction of regulatory T cells.Int Immunopharmacol 11:384-389.
Jiang C,Ting AT,Seed B(1998)PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines.Nature 391:82-86.
Joo IL,Lai AY,Bazzigaluppi P,Koletar MM,Dorr A,Brown ME,Thomason LA,Sled JG,McLaurin J,Stefanovic B(2017)Early neurovascular dysfunction in a transgenic rat model of Alzheimer’s disease.Sci Rep 7:46427.
Kidd BA,Wroblewska A,Boland MR,Agudo J,Merad M,Tatonetti NP,Brown BD,Dudley JT(2016)Mapping the effects of drugs on the immune system.Nat Biotechnol 34:47-54.
Kim KS,Kim HS,Park JM,Kim HW,Park MK,Lee HS,Lim DS,Lee TH,Chopp M,Moon J(2013)Long-term immunomodulatory effect of amniotic stem cells in an Alzheimer’s disease model.Neurobiol Aging 34:2408-2420.
Koch C,Brovkina L,Ruehl R,Worm M(2006)Immunomodulation by dietary n3-polyunsaturated acids(PUFA)in vitro.J Allergy Clin Immunol 117:S147.
Lambracht-Washington D,Rosenberg RN(2015)A noninflammatory immune response in aged DNA Aβ42-immunized mice supports its safety for possible immunotherapy in AD patients.Neurobiol Aging 36:1274-1281.
Lee HJ,Lee JK,Lee H,Carter JE,Chang JW,Oh W,Yang YS,Suh JG,Lee BH,Jin HK,Bae JS(2012)Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer’s disease mouse model through modulation of neuroinflammation.Neurobiol Aging33:588-602.
Lee SY,Chen SL,Chang YH,Chen PS,Huang SY,Tzeng NS,Wang LJ,Lee IH,Wang TY,Chen KC,Yang YK,Hong JS,Lu RB(2015)Low-dose memantine attenuated methadone dose in opioid-dependent patients:a 12-week double-blind randomized controlled trial.Sci Rep 5:10140.
Li C,Ebrahimi A,Schluesener H(2013)Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer’s disease.Ageing Res Rev 12:116-140.
Li Q,Lebson L,Lee DC,Nash K,Grimm J,Rosenthal A,Selenica ML,Morgan D,Gordon MN(2012)Chronological age impacts immunotherapy and monocyte uptake independent of amyloid load.J Neuroimmune Pharmacol 7:202-214.
Li Y,Yao J,Han C,Yang J,Chaudhry MT,Wang S,Liu H,Yin Y(2016)Quercetin,inflammation and immunity.Nutrients 8:167.
Liao YF,Wang BJ,Cheng HT,Kuo LH,Wolfe MS(2004)Tumor necrosis factor-alpha,interleukin-1beta,and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein though a JNK-dependent MAPK pathway.J Biol Chem 279:49523-49532.
Libro R,Giacoppo S,Soundara Rajan T,Bramanti P,Mazzon E(2016)Natural phytochemicals in the treatment and prevention of dementia:An oveview.Molecules 21:518.
Liu CY,Guo SD,Yu JZ,Li YH,Zhang H,Feng L,Chai Z,Yuan HJ,Yang WF,Feng QJ,Xiao BG,Ma CG(2015)Fasudil mediates cell therapy of EAE by immunomodulating encephalomyelitic T cells and macrophages.Eur J Immunol 45:142-152.
Liu DS,Liu WJ,Chen L,Ou XM,Wang T,Feng YL,Zhang SF,Xu D,Chen YJ,Wen FQ(2009)Rosiglitazone,a peroxisome proliferator-activated receptor-gamma agonist,attenuates acrolein-induced airway mucus hypersecretion in rats.Toxicology 260:112-119.
Loi F,Cordova LA,Zhang R,Pajarinen J,Lin TH,Goodman SB,Yao Z(2016)The effects of immunomodulation by macrophage subsets on osteogenesis in vitro.Stem Cell Res Ther 7:15.
Lowinus T,Bose T,Busse S,Busse M,Reinhold D,Schraven B,Bommhardt UH(2016)Immunomodulation by memantine in therapy of Alzheimer’s disease is mediated through inhibition of Kv1.3 channels and T cell responsiveness.Oncotarget 7:53797-53807.
Luz-Crawford P,Kurte M,Bravo-Alegría J,Contreras R,Nova-Lamperti E,Tejedor G,No?l D,Jorgensen C,Figueroa F,Djouad F,Carrión F(2013)Mesenchymal stem cells generate a CD4+CD25+Foxp3+regulatory T cell population during the differentiation process of Th1 and Th17 cells.Stem Cell Res Ther 4:65.
Mac Pherson KP,Sompol P,Kannarkat GT,Chang J,Sniffen L,Wildner ME,Norris CM,Tansey MG(2017)Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles,decreases beta-amyloid plaque load,and rescues impaired long-term potentiation in 5xFAD mice.Neurobiol Dis 102:81-95.
Magatti M,Vertua E,Cagnoni A,Silini A,Parolini O(2018)The immunomodulatory properties of amniotic cells:The two sides of the coin.Cell Transplant27:31-44.
Mandrekar-Colucci S,Landreth GE(2010)Microglia and inflammation in Alzheimer’s disease.CNS Neurol Disord Drug Targets 9:156-167.
Mc Geer PL,McGeer EG(2013)The amyloid cascade-inflammatory hypothesis of Alzheimer disease:implications for therapy.Acta Neuropathol 126:479-497.
Mecha M,FeliúA,I?igo PM,Mestre L,Carrillo-Salinas FJ,Guaza C(2013)Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis:a role for A2A receptors.Neurobiol Dis 59:141-150.
Medrano-Campillo P,Sarmiento-Soto H,álvarez-Sánchez N,álvarez-Ríos AI,Guerrero JM,Rodríguez-Prieto I,Castillo-Palma MJ,Lardone PJ,Carrillo-Vico A(2015)Evaluation of the immunomodulatory effect of melatonin on the T-cell response in peripheral blood from systemic lupus erythematosus patients.J Pineal Res 58:219-226.
Mimica N,Presecki P(2009)Side effects of approved antidementives.Psychiatr Danub 21:108-113.
Naj AC,Jun G,Beecham GW,Wang LS,Vardarajan BN,Buros J,Gallins PJ,Buxbaum JD,Jarvik GP,Crane PK,Larson EB,Bird TD,Boeve BF,Graff-Radford NR,De Jager PL,Evans D,Schneider JA,Carrasquillo MM,Ertekin-Taner N,Younkin SG,et al.(2011)Common variants at MS4A4/MS4A6E,CD2AP,CD33 and EPHA1 are associated with late-onset Alzheimer‘s disease.Nat Genet43:436-441.
Nedumpun T,Wongyanin P,Sirisereewan C,Ritprajak P,Palaga T,Thanawongnuwech R,Suradhat S(2017)Interleukin-1 receptor antagonist:an early immunomodulatory cytokine induced by porcine reproductive and respiratory syndrome virus.J Gen Virol 98:77-88.
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 26:10129-10140.
Oddo S,Caccamo A,Kitazawa M,Tseng BP,LaFerla FM(2003)Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease.Neurobiol Aging 24:1063-1070.
Ohtaki H,Ylostalo JH,Foraker JE,Robinson AP,Reger RL,Shioda S,Prockop DJ(2008)Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune responses.Proc Natl Acad Sci U S A 105:14638-14643.
Onos KD,Sukoff Rizzo SJ,Howell GR,Sasner M(2016)Toward more predictive genetic mouse models of Alzheimer’s disease.Brain Res Bull 122:1-11.
Parsa R,Andresen P,Gillett A,Mia S,Zhang XM,Mayans S,Holmberg D,Harris RA(2012)Adoptive transfer of imunomodulatory M2 macrophages prevents type 1 diabetes in NOD mice.Diabetes 61:2881-2892.
Parrish WR,Gallowitsch Puerta M,Ochani M,Ochani K,Moskovic D,Lin X,Czura CJ,Miller EJ,Al-Abed Y,Tracey KJ,Pavlov VA(2006)Choline suppresses inflammatory responses.Shock 25:45.
Parrish WR,Rosas-Ballina M,Gallowitsch-Puerta M,Ochani M,Ochani K,Yang LH,Hudson L,Lin X,Patel N,Johnson SM,Chavan S,Goldstein RS,Czura CJ,Miller EJ,Al-Abed Y,Tracey KJ,Pavlov VA(2008)Modulation of TNF release requiresα7 subunit nicotinic acetylcholine receptor-mediated signaling.Mol Med 14:567-574.
Pavlov VA,Wang H,Czura CJ,Friedman SG,Tracey KJ(2003)The cholinergic anti-inflammatory pathway:a missing link in neuroimmunomodulation.Mol Med 9:125-134.
Petrasek T,Skurlova M,Maleninska K,Vojtechova I,Kristofikova Z,Matuskova H,Sirova J,Vales K,Ripova D,Stuchlik A(2016)A rat model of Alzheimer’s disease based on Abeta42 and pro-oxidative substances exhibits cognitive deficit and alterations in glutamatergic and cholinergic neurotransmitter systems.Front Aging Neurosci 8:83.
Riedel WJ(2014)Preventing cognitive decline in preclinical Alzheimer’s disease.Curr Opin Pharmacol 14:18-22.
Rivera-Escalera F,Matousek SB,Ghosh S,Olschowka JA,O’Banion MK(2014)Inteleukin-1βmediated amyloid plaque clearance is independent of CCR2signaling in the APP/PS1 mouse model of Alzheimer’s disease.Neurobiol Dis69:124-133.
Rodgers G,Doucette CD,Spurrell DR,Hoskin DW,West KA,Liwski RS(2009)Immunomodulatory effect of piperine on dendritic cell function(50.36).J Immunol 182:50.36.
Rodriquez-Santiago L,Alí-Torres J,Vidossich P,Sodupe M(2015)Coordination properties of a metal chelator clioquinol to Zn(2+)studied by static DFT and ab initio molecular dynamics.Phys Chem Chem Phys 17:13582-13589.
Rosset MB,Lui G,Dansokho C,Chaigneau T,Dorothée G(2015)Vaccine-induced Aβ-specific CD8+T cells do not trigger autoimune neuroinflammation in a murine model of Alzheimer’s disease.J Neuroinflammation 12:95.
Rosshart SP,Vassallo BG,Angeletti D,Hutchinson DS,Morgan AP,Takeda K,Hickman HD,McCulloch JA,Badger JH,Ajami NJ,Trinchieri G,Pardo-Manuel de Villena F,Yewdell JW,Rehermann B(2017)Wild mouse gut microbiota promotes host fitness and improves disease resistance.Cell 171:1015-1028.
Rowley TJ,McKinstry A,Greenidge E,Smith W,Flood P(2010)Antinociceptive and anti-inflammatory effects of choline in a mouse model of postoperative pain.Br J Anaesth 105:201-207.
Sabogal-Guaqueta AM,Mu?oz-Manco JI,Ramírez-Pineda JR,Lamprea-Rodriguez M,Osorio E,Cardona-Gómez GP(2015)The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice.Neuropharmacology 93:134-145.
Saederup N,Cardona AE,Croft K,Mizutani M,Cotleur AC,Tsou CL,Ransohoff RM,Charo IF(2010)Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice.PLoS One5:e13693.
Sastre M,Walter J,Gentleman SM(2008)Interactions between APP secretases and inflammatory mediators.J Neuroinflammation 5:25.
Selkoe DJ(1991)The molecular pathology of Alzheimer’s disease.Neuron 6:487-498.
Serghides L,Patel SN,Ayi K,Lu Z,Gowda DC,Liles WC,Kain KC(2009)Rosiglitazone modulates the innate immune response to Plasmodium falciparum infection and improves outcome in experimental cerebral malaria.J Infect Dis199:1536-1545.
Sheng JG,Mrak RE,Griffin WS(1997)Neuritic plaque evolution in Alzheimer’s disease is accompanied by transition of activated microglia from primed to enlarged to phagocytic forms.Acta Neuropathol 94:1-5.
Shi M,Liu ZW,Wang FS(2011)Inmmunomodulatory properties and therapeutic application of mesenchymal stem cells.Clin Exp Immunol 164:1-8.
Shimada A,Hasegawa-Ishii S(2011)Senescence-accelerated Mice(SAMs)as a Model for Brain Aging and Immunosenescence.Aging Dis 2:414-435.
Singh S,Loke YK,Furberg CD(2011)Long-term use of thiazolidenediones and the associated risk of pneumonia or lower respiratory tract infection:systematic review and meta-analysis.Thorax 66:383-388.
Sinha AK,Bagchi AK(2004)Role of anti-CD3 in modulation of Th1-type immune response in Shigella dysenteriae infection.J Med Microbiol 53:1075-1081.
Song C,Zhang XY,Manku M(2009)Increased phospholipase A2 activity and inflammatory response but decreased nerve growth factor expression in the olfactory bulbectomized rat model of depression:effects of chronic ethyl-eicosapentaenoate treatment.J Neurosci 29:14-22.
Song Y,Chen X,Wang LY,Gao W,Zhu MJ(2013)Rho kinase inhibitor fasudil protects againstβ-amyloid-induced hippocampal neurodegeneration in rats.CNS Neurosci Ther 19:603-610.
Spires-Jones TL,Hyman BT(2014)The intersection of amyloid beta and tau synapses in Alzheimer’s disease.Neuron 82:756-771.
Sundaram JR,Poore CP,Sulaimee NHB,Pareek T,Cheong WF,Wenk MR,Pant HC,Frautschy SA,Low CM,Kesavapany S(2017)Curcumin ameliorates neuroinflammation,neurodegeneration,and memory deficits in p25 transgenic mousae model that bears hallmarks of Alzheimer’s disease.J Alzheimers Dis60:1429-1442.
Sunila ES,Kuttan G(2004)Immunomodulatory and antitumor activity of Piper longum Linn.and piperine.J Ethnopharmacol 90:339-346.
Thorlacius K,Slotta JE,Laschke MW,Wang Y,Menger MD,Jeppsson B,Thorlacius H(2006)Protective effect of fasudil,a Rho-kinase inhibitor,on chemokine expression,leukocyte recruitment,and hepatocellular apoptosis in septic liver injury.J Leukoc Biol 79:923-931.
Tong L,Prieto GA,Kramár EA,Smith ED,Cribbs DH,Lynch G,Cotman CW(2012)Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1βvia p38 mitogen-activated protein kinase.J Neurosci32:17714-17724.
Wang J,Lei X,Cheng XR,Zhang XR,Liu G,Cheng JP,Xu YR,Zeng J,Zhou WX,Zhang YX(2016)LW-AFC,a new formula derived from Liuwei Dihuang decoction,ameliorates behavioral and pathological deterioration via modulating the neuroendocrine-immune system in PrP-hAβPPswe/PS1ΔE9 transgenic mice..Alzheimer’s Res Ther 8:57.
Wang J,Zhang X,Cheng X,Cheng J,Liu F,Xu Y,Zeng J,Qiao S,Zhou W,Zhang Y(2017)LW-AFC,a new formula derived from Liuwei Dihuang decoction,ameliorates cognitive deterioration and modulates neuroendocrine-immune system in SAMP8 mouse.Curr Alzheimer Res 14:221-238.
Watkins LR,Milligan ED,Maier SF(2001)Glial activation:a driving force for pathological pain.Trends Neurosci 24:450-455.
Wisniewski T,Goni F(2014)Immunotherapy for Alzheimer’s disease.Biochem Pharmacol 88:499-507.
Yang Y,Cudaback E,Jorstad NL,Hemingway JF,Hagan CE,Melief EJ,Li X,Yoo T,Khademi SB,Montine KS,Montine TJ,Keene CD(2013)APOE3,but not APOE4,bone marrow transplantation mitigates behavioral and pathological changes in a mouse model of Alzheimer disease.Am J Pathol 183:905-917.
Yehuda S,Rabinovitz S(2014)Olfactory bulbectomy as a putative model for Alzheimer’:the protective role of essential fatty acids.PharmaNutrition 2:12-18.
Yu JZ,Li YH,Liu CY,Wang Q,Gu QF,Wang HQ,Zhang GX,Xiao BG,Ma CG(2017)Multitarget therapeutic effect of fasudil in APP/PS1 transgenic mice.CNS Neurological Disorders-Drug Targets 16:199-209.
Yu Y,Li X,Blanchard J,Li Y,Iqbal K,Liu F,Gong CX(2016)Insulin sensitizers improve learning and attenuate tau hyperphosphorylation and neuroinflammation in 3xTg-AD mice.J Neural Transm 122:593-606.
Zgair A,Lee JB,Wong JCM,Taha DA,Aram J,Di Virgilio D,McArthur JW,Cheng YK,Hennig IM,Barrett DA,Fischer PM,Constantinescu CS,Gershkovich P(2017)Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation.Sci Rep 7:14542.
Zhang YH,Raymick J,Sarkar S,Lahiri DK,Ray B,Holtzman D,Dumas M,Schmued LC(2013)Efficacy and toxicity of clioquinol treatment and A-beta42inoculation in the APP/PS1 mouse model of Alzheimer’s disease.Curr Alzheimer Res 10:494-506.
Zheng YZ,Deng G,Liang Q,Chen DF,Guo R,Lai RC(2017)Antioxidant activity of quercetin and its glucosides from propolis:A theoretical study.Sci Rep 7:7543.
Zhu D,Yang N,Liu YY,Zheng J,Ji C,Zuo PP(2016)M2 macrophage transplantation ameliorates cognitive dysfunction in amyloid-β-treated rats through regulation of microglial polarization.J Alzheimers Dis 52:483-495.
Zou C,Montagna E,Shi Y,Peters F,Blazquez-Llorca L,Shi S,Filser S,Dorostkar MM,Herms J(2015)Intraneuronal APP and extracellular Aβindependently cause dendritic spine pathology in transgenic mouse models of Alzheimer’s disease.Acta Neuropathol 129:909-920.
Zou C,Shi Y,Ohli J,Schüller U,Dorostkar MM,Herms J(2016)Neuroinflammation impairs adaptive structural plasticity of dendritic spines in a preclinical model of Alzheimer’s disease.Acta Neuropathol 131:235-246.