Modulating neuroinflammation in neurodegeneration-related dementia: can microglial toll-like receptors pull the plug?

Abbas N, Bednar I, Mix E, Marie S, Paterson D, Ljungberg A, Morris C, Winblad B, Nordberg A, Zhu J (2002) Up-regulation of the inflammatory cytokines IFN-γ and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APPSWE transgenic mice. J Neuroimmunol 126:50–57. https://doi.org/10.1016/S0165-5728(02)00050-4CrossRefPubMed

Abbas MM, Xu Z, Tan LC (2018) Epidemiology of Parkinson’s disease—east versus west. Mov Disord Clin Pract 5:14–28. https://doi.org/10.1002/mdc3.12568CrossRefPubMed

Alam JJ (2015) Selective brain-targeted antagonism of p38 MAPKα reduces hippocampal IL-1β levels and improves Morris water maze performance in aged rats. J Alzheimers Dis 48:219–227. https://doi.org/10.3233/JAD-150277CrossRefPubMedPubMedCentral

Alonso AD, Zaidi T, Grundke-Iqbal I, Iqbal K (1994) Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci USA 91:5562–5566. https://doi.org/10.1073/pnas.91.12.5562CrossRefPubMedPubMedCentral

Alonso AD, Grundke-Iqbal I, Iqbal K (1996) Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med 2:783–787. https://doi.org/10.1038/nm0796-783CrossRefPubMed

Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) An English translation of Alzheimer’s 1907 paper, “Über eine eigenartige Erkankung der Hirnrinde”. Clin Anat 8(6):429–431. https://doi.org/10.1002/ca.980080612

Alzheimer’s disease facts and figures (2020) Alzheimer’s & dementia: the journal of the Alzheimer's Association. Advance online publication. https://doi.org/10.1002/alz.12068

Amici SA, Dong J, Guerau-de-Arellano M (2017) Molecular mechanisms modulating the phenotype of macrophages and microglia. Front Immunol 8:1520. https://doi.org/10.3389/fimmu.2017.01520CrossRefPubMedPubMedCentral

Austin SA, d’Uscio LV, Katusic ZS (2013) Supplementation of nitric oxide attenuates AbPP and BACE1 protein in cerebral microcirculation of eNOS-deficient mice. J Alzheimers Dis 33:1–2. https://doi.org/10.3233/JAD-2012-121351CrossRef

Bakshi P, Margenthaler E, Reed J, Crawford F, Mullan M (2011) Depletion of CXCR2 inhibits γ-secretase activity and amyloid-β production in a murine model of Alzheimer’s disease. Cytokine 53:163–169. https://doi.org/10.1016/j.cyto.2010.10.008CrossRefPubMed

Bakunina N, Pariante CM, Zunszain PA (2015) Immune mechanisms linked to depression via oxidative stress and neuroprogression. Immunology 144:365–373. https://doi.org/10.1111/imm.12443CrossRefPubMedPubMedCentral

Balducci C, Frasca A, Zotti M, La Vitola P, Mhillaj E, Grigoli E, Iacobellis M, Grandi F, Messa M, Colombo L, Molteni M et al (2017) Toll-like receptor 4-dependent glial cell activation mediates the impairment in memory establishment induced by β-amyloid oligomers in an acute mouse model of Alzheimer’s disease. Brain Behav Immun 60:188–197. https://doi.org/10.1016/j.bbi.2016.10.012CrossRefPubMed

Bao Y, Cao X (2014) The immune potential and immunopathology of cytokine-producing B cell subsets: a comprehensive review. J Autoimmun 55:10–23. https://doi.org/10.1016/j.jaut.2014.04.001CrossRefPubMed

Belkhelfa M, Rafa H, Medjeber O, Arroul-Lammali A, Behairi N, Abada-Bendib M, Makrelouf M, Belarbi S, Masmoudi AN, Tazir M, Touil-Boukoffa C (2014) IFN-γ and TNF-α are involved during Alzheimer disease progression and correlate with nitric oxide production: a study in Algerian patients. J Interferon Cytokine Res 34:839–847. https://doi.org/10.1089/jir.2013.0085CrossRefPubMed

Benítez-Rivero S, Marín-Oyaga VA, García-Solís D, Huertas-Fernández I, García-Gómez FJ, Jesús S, Cáceres MT, Carrillo F, Ortiz AM, Carballo M, Mir P (2013) Clinical features and 123I-FP-CIT SPECT imaging in vascular parkinsonism and Parkinson's disease. J Neurol Neurosurg Psychiatry 84:122–129. https://doi.org/10.1136/jnnp-2012-302618CrossRefPubMed

Beutner KR (1995) Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. Antiviral Res 28:281–290. https://doi.org/10.1016/0166-3542(95)00066-6CrossRefPubMed

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

Braak H, de Vos RA, Bohl J, Del Tredici K (2006) Gastric α-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett 396:67–72. https://doi.org/10.1016/j.neulet.2005.11.012CrossRefPubMed

Braunstein MJ, Kucharczyk J, Adams S (2018) Targeting toll-like receptors for cancer therapy. Target Oncol 13:583–598. https://doi.org/10.1007/s11523-018-0589-7CrossRefPubMed

Butchi NB, Du M, Peterson KE (2010) Interactions between TLR7 and TLR9 agonists and receptors regulate innate immune responses by astrocytes and microglia. Glia 58:650–664. https://doi.org/10.1002/glia.20952CrossRefPubMedPubMedCentral

Capsoni S, Malerba F, Carucci NM, Rizzi C, Criscuolo C, Origlia N, Calvello M, Viegi A, Meli G, Cattaneo A (2017) The chemokine CXCL12 mediates the anti-amyloidogenic action of painless human nerve growth factor. Brain 140:201–217. https://doi.org/10.1093/brain/aww271CrossRefPubMed

Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, Ferrari C, Guerra UP, Paghera B, Muscio C, Bianchetti A et al (2017) Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging 49:60–68. https://doi.org/10.1016/j.neurobiolaging.2016.08.019CrossRefPubMed

Ceppa FA, Izzo L, Sardelli L, Raimondi I, Tunesi M, Albani D, Giordano C (2020) Human Gut-Microbiota Interaction in Neurodegenerative Disorders and Current Engineered Tools for Its Modeling. Front Cell Infect Microbiol 10:297. https://doi.org/10.3389/fcimb.2020.00297CrossRefPubMedPubMedCentral

Chassaing B, Gewirtz AT (2014) Pathobiont hypnotises enterocytes to promote tumour development. Gut 63:1837–1838. https://doi.org/10.1136/gutjnl-2014-306890CrossRefPubMed

Chandra G, Rangasamy SB, Roy A, Kordower JH, Pahan K (2016) Neutralization of RANTES and eotaxin prevents the loss of dopaminergic neurons in a mouse model of Parkinson disease. J Biol Chem 291:15267–15281. https://doi.org/10.1074/jbc.M116.714824

Chen H, O'Reilly EJ, Schwarzschild MA, Ascherio A (2008) Peripheral inflammatory biomarkers and risk of Parkinson's disease. Am J Epidemiol 167:90–95. https://doi.org/10.1093/aje/kwm260CrossRefPubMed

Cheng G, Cao Z, Xu X, Van Meir EG, Lambeth JD (2001) Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene 269:131–140. https://doi.org/10.1016/S0378-1119(01)00449-8CrossRefPubMed

Cherry JD, Olschowka JA, O’Banion MK (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 11:98. https://doi.org/10.1186/1742-2094-11-98CrossRefPubMedPubMedCentral

Cherry JD, Olschowka JA, O’Banion MK (2015) Arginase 1+ microglia reduce Aβ plaque deposition during IL-1β-dependent neuroinflammation. J Neuroinflammation 12:203. https://doi.org/10.1186/s12974-015-0411-8CrossRefPubMedPubMedCentral

Chotibut T, Davis RW, Arnold JC, Frenchek Z, Gurwara S, Bondada V, Geddes JW, Salvatore MF (2014) Ceftriaxone increases glutamate uptake and reduces striatal tyrosine hydroxylase loss in 6-OHDA Parkinson's model. Mol Neurobiol 49:1282–1292. https://doi.org/10.1007/s12035-013-8598-0CrossRefPubMed

Cipollini V, Anrather J, Orzi F, Iadecola C (2019) Th17 and Cognitive Impairment: Possible Mechanisms of Action. Front Neuroanat 13:95. https://doi.org/10.3389/fnana.2019.00095CrossRefPubMedPubMedCentral

Cooney SJ, Bermudez-Sabogal SL, Byrnes KR (2013) Cellular and temporal expression of NADPH oxidase (NOX) isotypes after brain injury J Neuroinflammation 10:917. https://doi.org/10.1186/1742-2094-10-155CrossRef

Corrêa SA, Eales KL (2012) The role of p38 MAPK and its substrates in neuronal plasticity and neurodegenerative disease. J Signal Transduct 2012:649079. https://doi.org/10.1155/2012/649079CrossRefPubMedPubMedCentral

Cristiano C, Volpicelli F, Lippiello P, Buono B, Raucci F, Piccolo M, Iqbal AJ, Irace C, Miniaci MC, Perrone Capano C, Calignano A, Mascolo N, Maione F (2019) Neutralization of IL-17 rescues amyloid-β-induced neuroinflammation and memory impairment. Br J Pharmacol 176:3544–3557. https://doi.org/10.1111/bph.14586CrossRefPubMedPubMedCentral

Daniele SG, Béraud D, Davenport C, Cheng K, Yin H, Maguire-Zeiss KA (2015) Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders. Sci. Signal 8:ra45. https://doi.org/10.1126/scisignal.2005965CrossRefPubMedPubMedCentral

Dayeh MA, Livadiotis G, Elaydi S (2018) A discrete mathematical model for the aggregation of β-Amyloid. PloS One 13(5). https://doi.org/10.1371/journal.pone.0196402

De Paola M, Buanne P, Biordi L, Bertini R, Ghezzi P, Mennini T (2007) Chemokine MIP-2/CXCL2, acting on CXCR2, induces motor neuron death in primary cultures. Neuroimmunomodulation 14:310–316. https://doi.org/10.1159/000123834CrossRefPubMed

Depino A, Ferrari C, Godoy MC, Tarelli R, Pitossi FJ (2005) Differential effects of interleukin-1β on neurotoxicity, cytokine induction and glial reaction in specific brain regions. J Neuroimmunol 168:96–110. https://doi.org/10.1016/j.jneuroim.2005.07.009CrossRefPubMed

Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J (2010) Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207:1067–1080. https://doi.org/10.1084/jem.20091419CrossRefPubMedPubMedCentral

Derk J, MacLean M, Juranek J, Schmidt AM (2018) The receptor for advanced glycation endproducts (RAGE) and mediation of inflammatory neurodegeneration. J Alzheimers Dis Parkinsonism 8:421. https://doi.org/10.4172/2161-0460.1000421CrossRefPubMedPubMedCentral

Devanand DP (2018) Viral hypothesis and antiviral treatment in Alzheimer’s disease. Curr Neurol Neurosci Rep 18:55. https://doi.org/10.1007/s11910-018-0863-1CrossRefPubMedPubMedCentral

Devos D, Lebouvier T, Lardeux B, Biraud M, Rouaud T, Pouclet H, Coron E, des Varannes SB, Naveilhan P, Nguyen JM, Neunlist M et al (2013) Colonic inflammation in Parkinson's disease. Neurobiol Dis 50:42–48. https://doi.org/10.1016/j.nbd.2012.09.007CrossRefPubMed

Dickson DW, Crystal HA, Mattiace LA, Masur DM, Blau AD, Davies P, Yen SH, Aronson MK (1992) Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging 13:179–189. https://doi.org/10.1016/0197-4580(92)90027-UCrossRefPubMed

DiSabato DJ, Quan N, Godbout JP (2016) Neuroinflammation: the devil is in the details. J Neurochem 139:136–153. https://doi.org/10.1111/jnc.13607CrossRefPubMedPubMedCentral

Doens D, Fernández PL (2014) Microglia receptors and their implications in the response to amyloid β for Alzheimer's disease pathogenesis. J Neuroinflammation 11:48. https://doi.org/10.1186/1742-2094-11-48CrossRefPubMedPubMedCentral

Doi Y, Mizuno T, Maki Y, Jin S, Mizoguchi H, Ikeyama M, Doi M, Michikawa M, Takeuchi H, Suzumura A (2009) Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid β neurotoxicity in in vitro and in vivo models of Alzheimer’s disease. Am J Pathol 175:2121–2132. https://doi.org/10.2353/ajpath.2009.090418CrossRefPubMedPubMedCentral

Dokmeci D (2004) Ibuprofen and Alzheimer's disease. Folia medica 46:5–10PubMed

Dorsey ER, Elbaz A, Nichols E, Abd-Allah F, Abdelalim A, Adsuar JC, Ansha MG et al (2018) Global, regional, and national burden of Parkinson's disease, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 17:939–953. https://doi.org/10.1016/S1474-4422(18)30295-3CrossRef

Drouin-Ouellet J, St-Amour I, Saint-Pierre M, Lamontagne-Proulx J, Kriz J, Barker RA, Cicchetti F (2015) Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson’s disease. Int J Neuropsychopharmacol 18:pyu103. https://doi.org/10.1093/ijnp/pyu103CrossRefPubMedCentral

Dzamko N, Gysbers A, Perera G, Bahar A, Shankar A, Gao J, Fu Y, Halliday GM (2017) Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol 133:303–319. https://doi.org/10.1007/s00401-016-1648-8CrossRefPubMed

Eacker SM, Dawson TM, Dawson VL (2009) Understanding microRNAs in neurodegeneration. Nat Rev Neurosci 10:837–841. https://doi.org/10.1038/nrn2726CrossRefPubMedPubMedCentral

Eriksen JL, Wszolek Z, Petrucelli L (2005) Molecular pathogenesis of Parkinson disease. Arch Neurol 62:353–357. https://doi.org/10.1001/archneur.62.3.353CrossRefPubMed

Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W, Wenning GK, Stefanova N (2013) Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia. Glia 61:349–360. https://doi.org/10.1002/glia.22437CrossRefPubMedPubMedCentral

Ferger B, Leng A, Mura A, Hengerer B, Feldon J (2004) Genetic ablation of tumor necrosis factor-alpha (TNF-α) and pharmacological inhibition of TNF-synthesis attenuates MPTP toxicity in mouse striatum. J Neurochem 89:822–833. https://doi.org/10.1111/j.1471-4159.2004.02399.xCrossRefPubMed

Ferrari CC, Godoy MC, Tarelli R, Chertoff M, Depino AM, Pitossi FJ (2006) Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1β in the substantia nigra. Neurobiol Dis 24:183–193. https://doi.org/10.1016/j.nbd.2006.06.013CrossRefPubMed

Field R, Campion S, Warren C, Murray C, Cunningham C (2010) Systemic challenge with the TLR3 agonist poly I: C induces amplified IFNα/β and IL-1β responses in the diseased brain and exacerbates chronic neurodegeneration. Brain Behav Immun 24:996–1007. https://doi.org/10.1016/j.bbi.2010.04.004CrossRefPubMedPubMedCentral

Förstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33:829–837. https://doi.org/10.1093/eurheartj/ehr304CrossRefPubMed

Fowler AJ, Hebron M, Missner AA, Wang R, Gao X, Kurd-Misto BT, Liu X, Moussa CE (2019) Multikinase ABL/DDR/SRC inhibition produces optimal effects for tyrosine kinase inhibition in neurodegeneration. Drugs R D 19:149–166. https://doi.org/10.1007/s40268-019-0266-zCrossRefPubMedPubMedCentral

Fuentealba P, Begum R, Capogna M, Jinno S, Marton LF, Csicsvari J, Thomson A, Somogyi P, Klausberger T (2008) Ivy cells: a population of nitric-oxide-producing, slow-spiking GABAergic neurons and their involvement in hippocampal network activity. Neuron 57:917–929. https://doi.org/10.1016/j.neuron.2008.01.034CrossRefPubMedPubMedCentral

Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Bouwman F, Venturelli E, Guidi I, Blankenstein MA, Bresolin N, Scarpini E (2006) Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. Arch Neurol 63:538–543. https://doi.org/10.1001/archneur.63.4.538CrossRefPubMed

Garry PS, Ezra M, Rowland MJ, Westbrook J, Pattinson KT (2015) The role of the nitric oxide pathway in brain injury and its treatment—from bench to bedside. Exp Neurol 263:235–243. https://doi.org/10.1016/j.expneurol.2014.10.017CrossRefPubMed

Garthwaite J (2008) Concepts of neural nitric oxide-mediated transmission. Eur J Neurosci 27:2783–2802. https://doi.org/10.1111/j.1460-9568.2008.06285.xCrossRefPubMedPubMedCentral

Gemma C, Catlow B, Cole M, Hudson C, Samec A, Shah N, Vila J, Bachstetter A, Bickford PC (2007) Early inhibition of TNFα increases 6-hydroxydopamine-induced striatal degeneration. Brain Res 1147:240–247. https://doi.org/10.1016/j.brainres.2007.02.003CrossRefPubMed

Gendelman HE, Zhang Y, Santamaria P, Olson KE, Schutt CR, Bhatti D, Shetty BL, Lu Y, Estes KA, Standaert DG, Heinrichs-Graham E et al (2017) Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial. NPJ Parkinsons Dis 3:1–12. https://doi.org/10.1038/s41531-017-0013-5CrossRef

Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, LaFerla FM, Olschowka JA, O'Banion MK (2013) Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model. J Neurosci 33:5053–5064. https://doi.org/10.1523/JNEUROSCI.4361-12.2013CrossRefPubMedPubMedCentral

Go M, Kou J, Lim JE, Yang J, Fukuchi KI (2016) Microglial response to LPS increases in wild-type mice during aging but diminishes in an Alzheimer's mouse model: implication of TLR4 signaling in disease progression. Biochem Biophys Res Commun 479:331–337. https://doi.org/10.1016/j.bbrc.2016.09.073CrossRefPubMedPubMedCentral

Gong T, Liu L, Jiang W, Zhou R (2019) DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol 26:1–8. https://doi.org/10.1038/s41577-019-0215-7CrossRef

Gupta V, Garg RK, Khattri S (2016) Levels of IL-8 and TNF-α decrease in Parkinson’s disease. Neurol Res 38:98–102. https://doi.org/10.1080/01616412.2015.1133026CrossRefPubMed

Gupta CL, Babu Khan M, Ampasala DR, Akhtar S, Dwivedi UN, Bajpai P (2019) Pharmacophore-based virtual screening approach for identification of potent natural modulatory compounds of human Toll-like receptor 7. J Biomol Struct Dyn 37:4721–4736. https://doi.org/10.1080/07391102.2018.1559098CrossRefPubMed

Guyon A, Skrzydelsi D, Rovere C, Rostene W, Parsadaniantz SM, Nahon JL (2006) Stromal cell-derived factor-1α modulation of the excitability of rat substantia nigra dopaminergic neurones: presynaptic mechanisms. J Neurochem 96:1540–1550. https://doi.org/10.1111/j.1471-4159.2006.03659.xCrossRefPubMed

Halliwell B (2012) Free radicals and antioxidants: updating a personal view. Nutr Rev 70:257–265. https://doi.org/10.1111/j.1753-4887.2012.00476.xCrossRefPubMed

Hampel H, Caraci F, Cuello AC, Caruso G, Nisticò R, Corbo M, Baldacci F, Toschi N, Garaci F, Chiesa PA, Verdooner SR et al (2020) A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease. Front Immunol 11:456. https://doi.org/10.3389/fimmu.2020.00456CrossRefPubMedPubMedCentral

Harach T, Marungruang N, Dutilleul N, Cheatham V, Mc Coy KD, Neher JJ, Jucker M, Fåk F, Bolmont T (2015) Reduction of Alzheimer's disease beta-amyloid pathology in the absence of gut microbiota. arXiv preprint arXiv:1509.02273. (https://arxiv.org/abs/1509.02273)

Hawkes CH, Del Tredici K, Braak H (2007) Parkinson's disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33:599–614. https://doi.org/10.1111/j.1365-2990.2007.00874.xCrossRefPubMedPubMedCentral

Hoehn MM, Yahr MD (1967) Parkinsonism: onset, progression, and mortality. Neurology 17:427–442. https://doi.org/10.1212/WNL.17.5.427CrossRefPubMed

Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Björklund T, Wang ZY, Roybon L, Melki R, Li JY (2014) Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 128:805–820. https://doi.org/10.1007/s00401-014-1343-6CrossRefPubMed

Horvath I, Iashchishyn IA, Forsgren L, Morozova-Roche LA (2017) Immunochemical Detection of α-Synuclein Autoantibodies in Parkinson's Disease: Correlation between Plasma and Cerebrospinal Fluid Levels. ACS Chem Neurosci 8:1170–1176. https://doi.org/10.1021/acschemneuro.7b00063CrossRefPubMed

Huang NQ, Jin H, Zhou SY, Shi JS, Jin F (2017) TLR4 is a link between diabetes and Alzheimer’s disease. Behav Brain Res 316:234–244. https://doi.org/10.1016/j.bbr.2016.08.047CrossRefPubMed

Ikeda-Matsuo Y (2017) The role of mPGES-1 in inflammatory brain diseases. Biol Pharm Bull 40:557–563. https://doi.org/10.1248/bpb.b16-01026CrossRefPubMed

Inoue K, Koizumi S, Kataoka A, Tozaki-Saitoh H, Tsuda M (2009) P2Y6-evoked microglial phagocytosis. Int Rev Neurobiol 85:159–163. https://doi.org/10.1016/S0074-7742(09)85012-5

Ismail S, Sturrock A, Wu P, Cahill B, Norman K, Huecksteadt T, Sanders K, Kennedy T, Hoidal J (2009) NOX4 mediates hypoxia-induced proliferation of human pulmonary artery smooth muscle cells: the role of autocrine production of transforming growth factor-β1 and insulin-like growth factor binding protein-3. Am J Physiol Lung Cell Mol Physiol 296:489–499. https://doi.org/10.1152/ajplung.90488.2008CrossRef

Iwakura Y, Ishigame H, Saijo S, Nakae S (2011) Functional specialization of interleukin-17 family members. Immunity 34:149–162. https://doi.org/10.1016/j.immuni.2011.02.012CrossRefPubMed

Izumi Y, Zorumski CF (1993) Nitric oxide and long-term synaptic depression in the rat hippocampus. Neuroreport 4:1131–1134PubMed

Jack CR, Petersen RC, Xu YC, O’Brien PC, Smith GE, Ivnik RJ, Boeve BF, Waring SC, Tangalos EG, Kokmen E (1999) Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 52:1397–1397. https://doi.org/10.1212/WNL.52.7.1397CrossRefPubMed

Jana M, Palencia CA, Pahan K (2008) Fibrillar amyloid-β peptides activate microglia via TLR2: implications for Alzheimer’s disease. J Immunol 181:7254–7262. https://doi.org/10.4049/jimmunol.181.10.7254CrossRefPubMed

Jayaraj RL, Rodriguez EA, Wang Y, Block ML (2017) Outdoor ambient air pollution and neurodegenerative diseases: the neuroinflammation hypothesis. Curr Environ Health Rep 4:166–179. https://doi.org/10.1007/s40572-017-0142-3CrossRefPubMed

Kalia LV, Lang AE (2016) Parkinson disease in 2015: evolving basic, pathological and clinical concepts in PD. Nat Rev Neurol 12:65–66. https://doi.org/10.1038/nrneurol.2015.249

Katzenschlager R, Head J, Schrag A, Ben-Shlomo Y, Evans A, Lees AJ (2008) Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD. Neurology 71:474–480. https://doi.org/10.1212/01.wnl.0000310812.43352.66CrossRefPubMed

Kesarwani P, Murali AK, Al-Khami AA, Mehrotra S (2013) Redox regulation of T-cell function: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal 18:1497–1534. https://doi.org/10.1089/ars.2011.4073CrossRefPubMedPubMedCentral

Kim C, Spencer B, Rockenstein E, Yamakado H, Mante M, Adame A, Fields JA, Masliah D, Iba M, Lee HJ, Rissman RA et al (2018) Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation. Mol Neurodegener 3:1–8. https://doi.org/10.1186/s13024-018-0276-2CrossRef

Kimura A, Yoshikura N, Hayashi Y, Inuzuka T (2018) Cerebrospinal fluid CC motif chemokine ligand 2 correlates with brain atrophy and cognitive impairment in Alzheimer’s disease. J Alzheimers Dis 61:581–588. https://doi.org/10.3233/JAD-170519CrossRefPubMed

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

Kobayashi Y (2010) The regulatory role of nitric oxide in proinflammatory cytokine expression during the induction and resolution of inflammation. J Leukoc Biol 88:1157–1162. https://doi.org/10.1189/jlb.0310149CrossRefPubMed

Kofler J, Wiley CA (2011) Microglia: key innate immune cells of the brain. Toxicol Pathol 39:103–114. https://doi.org/10.1177/0192623310387619CrossRefPubMed

Kuo CC, Liang SM, Liang CM (2006) CpG-B oligodeoxynucleotide promotes cell survival via up-regulation of Hsp70 to increase Bcl-xL and to decrease apoptosis-inducing factor translocation. J Biol Chem 281:38200–38207. https://doi.org/10.1074/jbc.M605439200CrossRefPubMed

Krauthausen M, Kummer MP, Zimmermann J, Reyes-Irisarri E, Terwel D, Bulic B, Heneka MT, Müller M (2015) CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model. J Clin Invest 125:365–378. https://doi.org/10.1172/JCI66771CrossRefPubMed

Kumar A, Singh A (2015) A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacol Rep 67:195–203. https://doi.org/10.1016/j.pharep.2014.09.004

Labzin LI, Heneka MT, Latz E (2018) Innate immunity and neurodegeneration. Annu Rev Med 69:437–449. https://doi.org/10.1146/annurev-med-050715-104343CrossRefPubMed

Lafon M, Megret F, Lafage M, Prehaud C (2006) The innate immune facet of brain human neurons express TLR-3 and sense viral dsRNA. J Mol Neurosci 29:185–194. https://doi.org/10.1385/JMN:29:3:185CrossRefPubMed

Laske C, Stellos K, Stransky E, Seizer P, Akcay Ö, Eschweiler GW, Leyhe T, Gawaz M (2008) Decreased plasma and cerebrospinal fluid levels of stem cell factor in patients with early Alzheimer's disease. J Alzheimers Dis 15:451–460. https://doi.org/10.3233/JAD-2008-15311CrossRefPubMed

Lehmann SM, Krüger C, Park B, Derkow K, Rosenberger K, Baumgart J, Trimbuch T, Eom G, Hinz M, Kaul D, Habbel P et al (2012) An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15:827–835. https://doi.org/10.1038/nn.3113CrossRefPubMed

Letiembre M, Liu Y, Walter S, Hao W, Pfander T, Wrede A, Schulz-Schaeffer W, Fassbender K (2009) Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. Neurobiol Aging 30:759–768. https://doi.org/10.1016/j.neurobiolaging.2007.08.018CrossRefPubMed

Limatola C, Ransohoff RM (2014) Modulating neurotoxicity through CX3CL1/CX3CR1 signaling. Front Cell Neurosci 8:229. https://doi.org/10.3389/fncel.2014.00229CrossRefPubMedPubMedCentral

Lin W, Ding M, Xue J, Leng W (2013) The role of TLR2/JNK/NF-κB pathway in amyloid β peptide-induced inflammatory response in mouse NG108-15 neural cells. Int Immunopharmacol 17:880–884. https://doi.org/10.1016/j.intimp.2013.09.016CrossRefPubMed

Liu YJ, Guo DW, Tian L, Shang DS, Zhao WD, Li B, Fang WG, Zhu L, Chen YH (2010) Peripheral T cells derived from Alzheimer's disease patients overexpress CXCR2 contributing to its transendothelial migration, which is microglial TNF-α-dependent. Neurobiol Aging 31:175–188. https://doi.org/10.1016/j.neurobiolaging.2008.03.024CrossRefPubMed

Liu HY, Hung YF, Lin HR, Yen TL, Hsueh YP (2017) Tlr7 deletion selectively ameliorates spatial learning but does not influence beta deposition and inflammatory response in an alzheimers disease mouse model. Neuropsychiatry 7:509–521. https://doi.org/10.4172/Neuropsychiatry.1000243CrossRef

Magalhaes J, Gegg ME, Migdalska-Richards A, Schapira AH (2018) Effects of ambroxol on the autophagy-lysosome pathway and mitochondria in primary cortical neurons. Sci Rep 8:1–2. https://doi.org/10.1038/s41598-018-19479-8CrossRef

Mancuso R, Fryatt G, Cleal M, Obst J, Pipi E, Monzón-Sandoval J, Ribe E, Winchester L, Webber C, Nevado A, Jacobs T et al (2019) CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain 142:3243–3264. https://doi.org/10.1093/brain/awz241CrossRefPubMedPubMedCentral

Martin HM, Campbell BJ, Hart CA, Mpofu C, Nayar M, Singh R, Englyst H, Williams HF, Rhodes JM (2004) Enhanced Escherichia coli adherence and invasion in Crohn's disease and colon cancer. Gastroenterology 127:80–93. https://doi.org/10.1053/j.gastro.2004.03.054CrossRefPubMed

Maskrey BH, Megson IL, Whitfield PD, Rossi AG (2011) Mechanisms of resolution of inflammation: a focus on cardiovascular disease. Arterioscler Thromb Vasc Biol 31:1001–1006. https://doi.org/10.1161/ATVBAHA.110.213850CrossRefPubMed

Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL (2015) Alzheimer's disease. Nat Rev Dis Primers 1:15056. https://doi.org/10.1038/nrdp.2015.56CrossRefPubMed

Matsumoto Y, Ohmori K, Fujiwara M (1992) Immune regulation by brain cells in the central nervous system: microglia but not astrocytes present myelin basic protein to encephalitogenic T cells under in vivo-mimicking conditions. Immunology 76:209–216PubMedPubMedCentral

Mayhan WG (2002) Cellular mechanisms by which tumor necrosis factor-α produces disruption of the blood–brain barrier. Brain Res 927:144–152. https://doi.org/10.1016/S0006-8993(01)03348-0CrossRefPubMed

McCabe K, Concannon RM, McKernan DP, Dowd E (2017) Time-course of striatal Toll-like receptor expression in neurotoxic, environmental and inflammatory rat models of Parkinson's disease. J Neuroimmunol 310:103–106. https://doi.org/10.1016/j.jneuroim.2017.07.007CrossRefPubMed

McDonald CL, Hennessy E, Rubio-Araiz A, Keogh B, McCormack W, McGuirk P, Reilly M, Lynch MA (2016) Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer’s disease. Brain Behav Immun 58:191–200. https://doi.org/10.1016/j.bbi.2016.07.143CrossRefPubMed

Merson TD, Binder MD, Kilpatrick TJ (2010) Role of cytokines as mediators and regulators of microglial activity in inflammatory demyelination of the CNS. Neuromolecular Med 12:99–132. https://doi.org/10.1007/s12017-010-8112-zCrossRefPubMed

Michell-Robinson MA, Moore CS, Healy LM, Osso LA, Zorko N, Grouza V, Touil H, Poliquin-Lasnier L, Trudelle AM, Giacomini PS, Bar-Or A, Antel JP (2015) Effects of fumarates on circulating and CNS myeloid cells in multiple sclerosis. Ann Clin Transl Neurol 3:27–41. https://doi.org/10.1002/acn3.270CrossRefPubMedPubMedCentral

Minter MR, Zhang C, Leone V, Ringus DL, Zhang X, Oyler-Castrillo P, Musch MW, Liao F, Ward JF, Holtzman DM, Chang EB (2016) Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci Rep 6:30028. https://doi.org/10.1038/srep30028CrossRefPubMedPubMedCentral

Moncada S, Bolaños JP (2006) Nitric oxide, cell bioenergetics and neurodegeneration. J Neurochem 97:1676–1689. https://doi.org/10.1111/j.1471-4159.2006.03988.xCrossRefPubMed

Moser B, Loetscher P (2001) Lymphocyte traffic control by chemokines. Nat Immunol 2:123–128. https://doi.org/10.1038/84219CrossRefPubMed

Moulignier A, Gueguen A, Lescure FX, Ziegler M, Girard PM, Cardon B, Pialoux G, Molina JM, Brandel JP, Lamirel C (2015) Does HIV infection alter Parkinson disease? J Acquir Immune Defic Syndr 70:129–136. https://doi.org/10.1097/QAI.0000000000000677CrossRefPubMed

Muniandy K, Gothai S, Badran KM, Suresh Kumar S, Esa NM, Arulselvan P (2018, 2018) Suppression of Proinflammatory Cytokines and Mediators in LPS-Induced RAW 264.7 Macrophages by Stem Extract of Alternanthera sessilis via the Inhibition of the NF-κB Pathway. J Immunol Res:3430684. https://doi.org/10.1155/2018/3430684

National institute of aging fact sheet on Alzheimer’s disease; content reviewed on May 22, 2019 and accessed on May 8, 2020 (https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet).

Nichols E, Szoeke CE, Vollset SE, Abbasi N, Abd-Allah F, Abdela J, Aichour MT, Akinyemi RO, Alahdab F, Asgedom SW, Awasthi A (2019) Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 18:88–106. https://doi.org/10.1016/S0140-6736(17)32154-2CrossRef

Nitsch L, Zimmermann J, Krauthausen M, Hofer MJ, Saggu R, Petzold GC, Heneka MT, Getts DR, Becker A, Campbell IL, Müller M (2019) CNS-Specific Synthesis of Interleukin 23 Induces a Progressive Cerebellar Ataxia and the Accumulation of Both T and B Cells in the Brain: Characterization of a Novel Transgenic Mouse Model. Mol Neurobiol 56:7977–7993. https://doi.org/10.1007/s12035-019-1640-0CrossRefPubMed

Noelker C, Morel L, Lescot T, Osterloh A, Alvarez-Fischer D, Breloer M, Henze C, Depboylu C, Skrzydelski D, Michel PP, Dodel RC et al (2013) Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease. Sci Rep 3:1393. https://doi.org/10.1038/srep01393CrossRefPubMedPubMedCentral

O'Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer's disease. Annu Rev Neurosci 34:185–204. https://doi.org/10.1146/annurev-neuro-061010-113613CrossRefPubMedPubMedCentral

Okun E, Griffioen KJ, Mattson MP (2011) Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 34:269–281. https://doi.org/10.1016/j.tins.2011.02.005CrossRefPubMedPubMedCentral

Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725. https://doi.org/10.1016/s1074-7613(00)00070-4CrossRefPubMed

Ottonello L, Morone MP, Dapino P, Dallegri F (1995) Cyclic AMP-elevating agents down-regulate the oxidative burst induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) in adherent neutrophils. Clin Exp Immunol 101:502–506. https://doi.org/10.1111/j.1365-2249.1995.tb03141.xCrossRefPubMedPubMedCentral

Pabon MM, Bachstetter AD, Hudson CE, Gemma C, Bickford PC (2011) CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson's disease. J Neuroinflammation 8:9. https://doi.org/10.1186/1742-2094-8-9CrossRefPubMedPubMedCentral

Pagan FL, Hebron ML, Wilmarth B, Torres-Yaghi Y, Lawler A, Mundel EE, Yusuf N, Starr NJ, Arellano J, Howard HH, Peyton M et al (2019) Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson's disease. Pharmacol Res Perspect 7:e00470. https://doi.org/10.1002/prp2.470CrossRefPubMedPubMedCentral

Pak T, Cadet P, Mantione KJ, Stefano GB (2005) Morphine via nitric oxide modulates beta-amyloid metabolism: a novel protective mechanism for Alzheimer's disease. Med Sci Monit 11:BR357–BR366PubMed

Parathath SR, Parathath S, Tsirka SE (2006) Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice. J Cell Sci 119:339–349. https://doi.org/10.1242/jcs.02734CrossRefPubMed

Park KM, Bowers WJ (2010) Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal 22:977–983. https://doi.org/10.1016/j.cellsig.2010.01.010CrossRefPubMedPubMedCentral

Perl DP (2010) Neuropathology of Alzheimer's disease. Mt Sinai J Med 77:32–42. https://doi.org/10.1002/msj.20157CrossRefPubMedPubMedCentral

Persaud-Sawin DA, Banach L, Harry GJ (2009) Raft aggregation with specific receptor recruitment is required for microglial phagocytosis of Aβ42. Glia 57:320–335. https://doi.org/10.1002/glia.20759CrossRefPubMedPubMedCentral

Pifarré P, Prado J, Giralt M, Molinero A, Hidalgo J, Garcia A (2010) Cyclic GMP phosphodiesterase inhibition alters the glial inflammatory response, reduces oxidative stress and cell death and increases angiogenesis following focal brain injury. J Neurochem 112:807–817. https://doi.org/10.1111/j.1471-4159.2009.06518.xCrossRefPubMed

Pisa D, Alonso R, Rábano A, Rodal I, Carrasco L (2015) Different brain regions are infected with fungi in Alzheimer’s disease. Sci Rep 5:15015. https://doi.org/10.1038/srep15015CrossRefPubMedPubMedCentral

Prorok-Hamon M, Friswell MK, Alswied A, Roberts CL, Song F, Flanagan PK, Knight P, Codling C, Marchesi JR, Winstanley C, Hall N, Rhodes JM, Campbell BJ (2014) Colonic mucosa-associated diffusely adherent afaC+ Escherichia coli expressing lpfA and pks are increased in inflammatory bowel disease and colon cancer. Gut 63:761–770. https://doi.org/10.1136/gutjnl-2013-304739CrossRefPubMed

Proescholdt MG, Chakravarty S, Foster JA, Foti SB, Briley EM, Herkenham M (2002) Intracerebroventricular but not intravenous interleukin-1β induces widespread vascular-mediated leukocyte infiltration and immune signal mRNA expression followed by brain-wide glial activation. Neuroscience 112:731–749. https://doi.org/10.1016/S0306-4522(02)00048-9CrossRefPubMed

Qin Y, Liu Y, Hao W, Decker Y, Tomic I, Menger MD, Liu C, Fassbender K (2016) Stimulation of TLR4 attenuates Alzheimer’s disease–related symptoms and pathology in tau-transgenic mice. J Immunol 197:3281–3292. https://doi.org/10.4049/jimmunol.1600873CrossRefPubMed

Qiu Z, Gruol DL (2003) Interleukin-6, β-amyloid peptide and NMDA interactions in rat cortical neurons. J Neuroimmunol 139:51–57. https://doi.org/10.1016/S0165-5728(03)00158-9CrossRefPubMed

Quintanilla RA, Orellana DI, González-Billault C, Maccioni RB (2004) Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res 295:245–257. https://doi.org/10.1016/j.yexcr.2004.01.002CrossRefPubMed

Raman D, Milatovic SZ, Milatovic D, Splittgerber R, Fan GH, Richmond A (2011) Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1α, suppress amyloid β-induced neurotoxicity. Toxicol Appl Pharmacol 256:300–313. https://doi.org/10.1016/j.taap.2011.06.006CrossRefPubMedPubMedCentral

Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Invest 122:1164–1171. https://doi.org/10.1172/JCI58644CrossRefPubMedPubMedCentral

Ran Z, Yue-Bei L, Qiu-Ming Z, Huan Y (2020) Regulatory B Cells and Its Role in Central Nervous System Inflammatory Demyelinating Diseases. Front Immunol 11:1884. https://doi.org/10.3389/fimmu.2020.01884CrossRefPubMedPubMedCentral

Ray PD, Huang BW, Tsuji Y (2012) Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24:981–990. https://doi.org/10.1016/j.cellsig.2012.01.008CrossRefPubMedPubMedCentral

Reale M, Iarlori C, Thomas A, Gambi D, Perfetti B, Di Nicola M, Onofrj M (2009) Peripheral cytokines profile in Parkinson’s disease. Brain Behav Immun 23:55–63. https://doi.org/10.1016/j.bbi.2008.07.003CrossRefPubMed

Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE (2009) CD14 and toll-like receptors 2 and 4 are required for fibrillar Aβ-stimulated microglial activation. J Neurosci 29:11982–11992. https://doi.org/10.1523/JNEUROSCI.3158-09.2009CrossRefPubMedPubMedCentral

Robertson CS, Gopinath SP, Valadka AB, Van M, Swank PR, Goodman JC (2011) Variants of the endothelial nitric oxide gene and cerebral blood flow after severe traumatic brain injury. J Neurotrauma 28:727–737. https://doi.org/10.1089/neu.2010.1476CrossRefPubMedPubMedCentral

Rocha NP, Scalzo PL, Barbosa IG, Souza MS, Morato IB, Vieira ÉL, Christo PP, Teixeira AL, Reis HJ (2014) Cognitive status correlates with CXCL10/IP-10 levels in Parkinson’s disease. Parkinsons Dis 2014:903796. https://doi.org/10.1155/2014/903796CrossRefPubMedPubMedCentral

Roodveldt C, Labrador-Garrido A, Gonzalez-Rey E, Lachaud CC, Guilliams T, Fernandez-Montesinos R, Benitez-Rondan A, Robledo G, Hmadcha A, Delgado M, Dobson CM, Pozo D (2013) Preconditioning of microglia by α-synuclein strongly affects the response induced by toll-like receptor (TLR) stimulation. PloS one 8:e79160. https://doi.org/10.1371/journal.pone.0079160CrossRefPubMedPubMedCentral

Ros-Bernal F, Hunot S, Herrero MT, Parnadeau S, Corvol JC, Lu L, Alvarez-Fischer D, Carrillo-de Sauvage MA, Saurini F, Coussieu C, Kinugawa K (2011) Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism. Proc Natl Acad Sci USA 108:6632–6637. https://doi.org/10.1073/pnas.1017820108CrossRefPubMedPubMedCentral

Ross GW, Petrovitch H, Abbott RD (2004) Parkinsonian signs and substantia nigra neuron density in descendants elders without PD. Ann Neurol 56:532–539. https://doi.org/10.1002/ana.20226CrossRefPubMed

Rostène W, Kitabgi P, Parsadaniantz SM (2007) Chemokines: a new class of neuromodulator? Nat Rev Neurosci 8:895–903. https://doi.org/10.1038/nrn2255CrossRefPubMed

Ryan NS, Rossor MN, Fox NC (2015) Alzheimer’s disease in the 100 years since Alzheimer’s death. Brain 138:3816–3821. https://doi.org/10.1093/brain/awv316CrossRefPubMed

Sabatino JJ Jr, Pröbstel AK, Zamvil SS (2019) B cells in autoimmune and neurodegenerative central nervous system diseases. Nat Rev Neurosci 20:728–745. https://doi.org/10.1038/s41583-019-0233-2CrossRefPubMed

Sawyer AJ, Tian W, Saucier-Sawyer JK, Rizk PJ, Saltzman WM, Bellamkonda RV, Kyriakides TR (2014) The effect of inflammatory cell-derived MCP-1 loss on neuronal survival during chronic neuroinflammation. Biomaterials 35:6698–6706. https://doi.org/10.1016/j.biomaterials.2014.05.008CrossRefPubMedPubMedCentral

Schetters ST, Gomez-Nicola D, Garcia-Vallejo JJ, Van Kooyk Y (2018) Neuroinflammation: microglia and T cells get ready to tango. Front Immunol 8:1905. https://doi.org/10.3389/fimmu.2017.01905CrossRefPubMedPubMedCentral

Scholtzova H, Chianchiano P, Pan J, Sun Y, Goñi F, Mehta PD (2014) Wisniewski T. Amyloid β and Tau Alzheimer's disease related pathology is reduced by Toll-like receptor 9 stimulation. Acta Neuropathol Commun 2:101. https://doi.org/10.1186/s40478-014-0101-2CrossRefPubMedPubMedCentral

Seidel K, Mahlke J, Siswanto S, Krüger R, Heinsen H, Auburger G, den Dunnen W (2015) The brainstem pathologies of Parkinson's disease and dementia with Lewy bodies. Brain Pathol 25:121–135. https://doi.org/10.1111/bpa.12168CrossRefPubMed

Semple BD, Bye N, Ziebell JM, Morganti-Kossmann MC (2010) Deficiency of the chemokine receptor CXCR2 attenuates neutrophil infiltration and cortical damage following closed head injury. Neurobiol Dis 40:394–403. https://doi.org/10.1016/j.nbd.2010.06.015CrossRefPubMed

Shaftel SS, Griffin WS, O'Banion MK (2008) The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation:5–7. https://doi.org/10.1186/1742-2094-5-7

Sochocka M, Diniz BS, Leszek J (2017) Inflammatory response in the CNS: friend or foe? Mol Neurobiol 54:8071–8089. https://doi.org/10.1007/s12035-016-0297-1CrossRefPubMed

Solleiro-Villavicencio H, Rivas-Arancibia S (2018) Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4⁺T Cells in Neurodegenerative Diseases. Front Cell Neurosci 12:114. https://doi.org/10.3389/fncel.2018.00114CrossRefPubMedPubMedCentral

Söllvander S, Ekholm-Pettersson F, Brundin RM, Westman G, Kilander L, Paulie S, Lannfelt L, Sehlin D (2015) Increased Number of Plasma B Cells Producing Autoantibodies Against Aβ42 Protofibrils in Alzheimer's Disease. J Alzheimers Dis 48:63–72. https://doi.org/10.3233/JAD-150236CrossRefPubMedPubMedCentral

Sokolova A, Hill MD, Rahimi F, Warden LA, Halliday GM, Shepherd CE (2009) Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer's disease. Brain Pathol 19:392–398. https://doi.org/10.1111/j.1750-3639.2008.00188.xCrossRefPubMed

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

Spooren A, Kolmus K, Laureys G, Clinckers R, De Keyser J, Haegeman G, Gerlo S (2011) Interleukin-6, a mental cytokine. Brain Research Rev 67:157–183. https://doi.org/10.1016/j.brainresrev.2011.01.002CrossRef

St-Amour I, Bosoi CR, Paré I, Ignatius Arokia Doss PM, Rangachari M, Hébert SS, Bazin R, Calon F (2019) Peripheral adaptive immunity of the triple transgenic mouse model of Alzheimer's disease. J Neuroinflammation 16:3. https://doi.org/10.1186/s12974-018-1380-5CrossRefPubMedPubMedCentral

Steinert JR, Chernova T, Forsythe ID (2010) Nitric oxide signaling in brain function, dysfunction, and dementia. Neuroscientist 16:435–452. https://doi.org/10.1177/1073858410366481CrossRefPubMed

Stewart CR, Stuart LM, Wilkinson K, Van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A et al (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11:155–161. https://doi.org/10.1038/ni.1836CrossRefPubMed

Stojkovska I, Krainc D, Mazzulli JR (2018) Molecular mechanisms of α-synuclein and GBA1 in Parkinson’s disease. Cell Tissue Res 373:51–60. https://doi.org/10.1007/s00441-017-2704-yCrossRefPubMed

Subramanian S, Ayala P, Wadsworth TL, Harris CJ, Vandenbark AA, Quinn JF, Offner H (2010) CCR6: a biomarker for Alzheimer's-like disease in a triple transgenic mouse model. J Alzheimers Dis 22:619–629. https://doi.org/10.3233/JAD-2010-100852CrossRefPubMedPubMedCentral

Tabrez S, Jabir NR, Shakil S, Greig NH, Alam Q, Abuzenadah AM, Damanhouri GA, Kamal MA (2012) A synopsis on the role of tyrosine hydroxylase in Parkinson's disease. CNS Neurol Disord Drug Targets 11:395–409. https://doi.org/10.2174/187152712800792785CrossRefPubMedPubMedCentral

Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi KI (2006) Role of toll-like receptor signalling in Aβ uptake and clearance. Brain 129:3006–3019. https://doi.org/10.1093/brain/awl249CrossRefPubMed

Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1–4. https://doi.org/10.1093/intimm/dxh186CrossRefPubMed

Tan KH, Harrington S, Purcell WM, Hurst RD (2004) Peroxynitrite mediates nitric oxide–induced blood–brain barrier damage. Neurochem Res 29:579–587. https://doi.org/10.1023/B:NERE.0000014828.32200.bdCrossRefPubMed

Tang P, Chong L, Li X, Liu Y, Liu P, Hou C, Li R (2014) Correlation between serum RANTES levels and the severity of Parkinson’s disease. Oxid Med Cell Longev 2014:208408. https://doi.org/10.1155/2014/208408CrossRefPubMedPubMedCentral

Thome AD, Standaert DG, Harms AS (2015) Fractalkine signaling regulates the inflammatory response in an α-synuclein model of Parkinson disease. PLoS One 10:10. https://doi.org/10.1371/journal.pone.0140566CrossRef

Thompson WL, Karpus WJ, Van Eldik LJ (2008) MCP-1-deficient mice show reduced neuroinflammatory responses and increased peripheral inflammatory responses to peripheral endotoxin insult. J Neuroinflammation

Tiwari RK, Chandrakar P, Gupta CL, Sayyed U, Shekh R, Bajpai P (2020) Leishmanial CpG DNA nanovesicles: A propitious prophylactic approach against visceral leishmaniasis. Int Immunopharmacol 90:107181. https://doi.org/10.1016/j.intimp.2020.107181

Tobinick EL, Gross H (2008) Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation 5:2. https://doi.org/10.1186/1742-2094-5-2CrossRefPubMedPubMedCentral

Tripathy D, Thirumangalakudi L, Grammas P (2010) RANTES upregulation in the Alzheimer's disease brain: a possible neuroprotective role. Neurobiol Aging 31:8–16. https://doi.org/10.1016/j.neurobiolaging.2008.03.009CrossRefPubMed

Tse HM, Milton MJ, Schreiner S, Profozich JL, Trucco M, Piganelli JD (2007) Disruption of innate-mediated proinflammatory cytokine and reactive oxygen species third signal leads to antigen-specific hyporesponsiveness. J Immunol 178(2):908–917

Twelves D, Perkins KS, Counsell C (2003) Systematic review of incidence studies of Parkinson’s disease. Mov Disord 18:19–31. https://doi.org/10.1002/mds.10305

Umezawa N, Kawahata K, Mizoguchi F, Kimura N, Yoshihashi-Nakazato Y, Miyasaka N, Kohsaka H (2018) Interleukin-23 as a therapeutic target for inflammatory myopathy. Sci Rep 8:5498. https://doi.org/10.1038/s41598-018-23539-4CrossRefPubMedPubMedCentral

Venezia S, Refolo V, Polissidis A, Stefanis L, Wenning GK, Stefanova N (2017) Toll-like receptor 4 stimulation with monophosphoryl lipid A ameliorates motor deficits and nigral neurodegeneration triggered by extraneuronal α-synucleinopathy. Mol Neurodegener 12:52. https://doi.org/10.1186/s13024-017-0195-7CrossRefPubMedPubMedCentral

Viedt C, Dechend R, Fei J, Hänsch GM, Kreuzer J, Orth SR (2002) MCP-1 induces inflammatory activation of human tubular epithelial cells: involvement of the transcription factors, nuclear factor-κB and activating protein-1. J Am Soc Nephrol 13:1534–1547. https://doi.org/10.1097/01.ASN.0000015609.31253.7FCrossRefPubMed

Villarán RF, Espinosa-Oliva AM, Sarmiento M, De Pablos RM, Argüelles S, Delgado-Cortés MJ, Sobrino V, Van Rooijen N, Venero JL, Herrera AJ, Cano J (2010) Ulcerative colitis exacerbates lipopolysaccharide-induced damage to the nigral dopaminergic system: potential risk factor in Parkinsons disease. J Neurochem 114:1687–1700. https://doi.org/10.1111/j.1471-4159.2010.06879.xCrossRefPubMed

Vollmar P, Kullmann JS, Thilo B, Claussen MC, Rothhammer V, Jacobi H, Sellner J, Nessler S, Korn T, Hemmer B (2010) Active immunization with amyloid-β 1–42 impairs memory performance through TLR2/4-dependent activation of the innate immune system. J Immunol 185:6338–6347. https://doi.org/10.4049/jimmunol.1001765CrossRefPubMed

Wang X, Chi J, Huang D, Ding L, Zhao X, Jiang L, Yu Y, Gao F (2020) α-synuclein promotes progression of Parkinson's disease by upregulating autophagy signaling pathway to activate NLRP3 inflammasome. Exp Ther Med 19:931–938. https://doi.org/10.3892/etm.2019.8297CrossRefPubMed

Weintraub MK, Kranjac D, Eimerbrink MJ, Pearson SJ, Vinson BT, Patel J, Summers WM, Parnell TB, Boehm GW, Chumley MJ (2014) Peripheral administration of poly I: C leads to increased hippocampal amyloid-beta and cognitive deficits in a non-transgenic mouse. Behav Brain Res 266:183–187. https://doi.org/10.1016/j.bbr.2014.03.009CrossRefPubMed

WHO fact sheet on Dementia (2019) https://www.who.int/news-room/fact-sheets/detail/dementia. Accessed 07 May 2020

Witowski J, Książek K, Jörres A (2004) Interleukin-17: a mediator of inflammatory responses. Cell Mol Life Sci 61:567–579. https://doi.org/10.1007/s00018-003-3228-zCrossRefPubMed

Woulfe JM, Gray MT, Gray DA, Munoz DG, Middeldorp JM (2014) Hypothesis: a role for EBV-induced molecular mimicry in Parkinson's disease. Parkinsonism Relat Disord 20:685–694. https://doi.org/10.1016/j.parkreldis.2014.02.031CrossRefPubMed

Wu HM, Zhang LF, Ding PS, Liu YJ, Wu X, Zhou JN (2014) Microglial activation mediates host neuronal survival induced by neural stem cells. J Cell Mol Med 18:1300–1312. https://doi.org/10.1111/jcmm.12281CrossRefPubMedPubMedCentral

Wu WY, Kang KH, Chen SS, Chiu SH, Yen AF, Fann JY, Su CW, Liu HC, Lee CZ, Fu WM, Chen HH, Lio HH (2015) Hepatitis C virus infection: a risk factor for Parkinson's disease. J Viral Hepat 22:784–791. https://doi.org/10.1111/jvh.12392CrossRefPubMed

Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496:445–455. https://doi.org/10.1038/nature12034CrossRefPubMedPubMedCentral

Xconomy news report dated: September 28 (2014) last accessed on May 29, 2020 [https://xconomy.com/boston/2014/09/26/blessed-by-angels-gliacure-tests-new-alzheimers-approach-in-humans/]

Xue Q, Yan Y, Zhang R, Xiong H (2018) Regulation of iNOS on immune cells and its role in diseases. Int J Mol Sci 19:3805. https://doi.org/10.3390/ijms19123805CrossRefPubMedCentral

Yang G, Meng Y, Li W, Yong Y, Fan Z, Ding H, Wei Y, Luo J, Ke ZJ (2011) Neuronal MCP-1 mediates microglia recruitment and neurodegeneration induced by the mild impairment of oxidative metabolism. Brain Pathol 21:279–297. https://doi.org/10.1111/j.1750-3639.2010.00445.xCrossRefPubMed

Yimer EM, Hishe HZ, Tuem KB (2019) Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review. Front Neurosci 13. https://doi.org/10.3389/fnins.2019.00236

Yoshimura T, Matsushima K, Oppenheim JJ, Leonard EJ (1987) Neutrophil chemotactic factor produced by lipopolysaccharide (LPS)-stimulated human blood mononuclear leukocytes: partial characterization and separation from interleukin 1 (IL 1). J Immunol 139:788–793PubMed

Zaheer S, Thangavel R, Wu Y, Khan MM, Kempuraj D, Zaheer A (2013) Enhanced expression of glia maturation factor correlates with glial activation in the brain of triple transgenic Alzheimer’s disease mice. Neurochem Res 38:218–225. https://doi.org/10.1007/s11064-012-0913-zCrossRefPubMed

Zenaro E, Pietronigro E, Della Bianca V, Piacentino G, Marongiu L, Budui S, Turano E, Rossi B, Angiari S, Dusi S, Montresor A, Carlucci T, Nanì S, Tosadori G, Calciano L, Catalucci D, Berton G, Bonetti B, Constantin G (2015) Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med 21:880–886. https://doi.org/10.1038/nm.3913CrossRefPubMed

Zhang C, Griciuc A, Hudry E, Wan Y, Quinti L, Ward J, Forte AM, Shen X, Ran C, Elmaleh DR, Tanzi RE (2018) Cromolyn reduces levels of the Alzheimer’s disease-associated amyloid β-protein by promoting microglial phagocytosis. Sci Rep 8:1–9. https://doi.org/10.1038/s41598-018-19641-2CrossRef

Zhang B, Wang HE, Bai YM, Tsai SJ, Su TP, Chen TJ, Wang YP, Chen MH (2021) Inflammatory bowel disease is associated with higher dementia risk: a nationwide longitudinal study. Gut 70:85–91. https://doi.org/10.1136/gutjnl-2020-320789CrossRefPubMed

Zhao J, O'Connor T, Vassar R (2011) The contribution of activated astrocytes to Aβ production: implications for Alzheimer's disease pathogenesis. J Neuroinflammation 8:150. https://doi.org/10.1186/1742-2094-8-150CrossRefPubMedPubMedCentral

Zhou P, Weng R, Chen Z, Wang R, Zou J, Liu X, Liao J, Wang Y, Xia Y, Wang Q (2016) TLR4 Signaling in MPP⁺-Induced Activation of BV-2 Cells. Neural Plast:5076740. https://doi.org/10.1155/2016/5076740

At a glance: The STEP trials

Springer Medicine

Modulating neuroinflammation in neurodegeneration-related dementia: can microglial toll-like receptors pull the plug?

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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