On the Possible Relevance of Bottom-up Pathways in the Pathogenesis of Alzheimer’s Disease

Author(s): Friedrich Leblhuber, Kostja Steiner, Simon Geisler, Dietmar Fuchs*, Johanna M. Gostner

Journal Name: Current Topics in Medicinal Chemistry

Volume 20 , Issue 15 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Dementia is an increasing health problem in older aged populations worldwide. Age-related changes in the brain can be observed decades before the first symptoms of cognitive decline appear. Cognitive impairment has chronic inflammatory components, which can be enhanced by systemic immune activation. There exist mutual interferences between inflammation and cognitive deficits. Signs of an activated immune system i.e. increases in the serum concentrations of soluble biomarkers such as neopterin or accelerated tryptophan breakdown along the kynurenine axis develop in a significant proportion of patients with dementia and correlate with the course of the disease, and they also have a predictive value. Changes in biomarker concentrations are reported to be associated with systemic infections by pathogens such as cytomegalovirus (CMV) and bacterial content in saliva. More recently, the possible influence of microbiome composition on Alzheimer’s disease (AD) pathogenesis has been observed. These observations suggest that brain pathology is not the sole factor determining the pathogenesis of AD. Interestingly, patients with AD display drastic changes in markers of immune activation in the circulation and in the cerebrospinal fluid. Other data have suggested the involvement of factors extrinsic to the brain in the pathogenesis of AD. However, currently, neither the roles of these factors nor their importance has been clearly defined.

Keywords: Alzheimer's dementia, Cognitive impairment, Cytomegalovirus, Kynurenine axis, Microbiome, Neopterin, Pathogenesis.

Fratiglioni, L.; De Ronchi, D.; Agüero-Torres, H. Worldwide prevalence and incidence of dementia. Drugs Aging, 1999, 15(5), 365-375.
[http://dx.doi.org/10.2165/00002512-199915050-00004] [PMID: 10600044]
Barnes, D.E.; Yaffe, K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol., 2011, 10(9), 819-828.
[http://dx.doi.org/10.1016/S1474-4422(11)70072-2] [PMID: 21775213]
Bangen, K.J.; Clark, A.L.; Edmonds, E.C.; Evangelista, N.D.; Werhane, M.L.; Thomas, K.R.; Locano, L.E.; Tran, M.; Zlatar, Z.Z.; Nation, D.A.; Bondi, M.W.; Delano-Wood, L. Cerebral blood flow and amyloid-ß interact to affect memory performance in cognitively normal older adults. Front. Aging Neurosci., 2017, 9, 181.
[http://dx.doi.org/10.3389/fnagi.2017.00181] [PMID: 28642699]
Widner, B.; Leblhuber, F.; Walli, J.; Tilz, G.P.; Demel, U.; Fuchs, D. Tryptophan degradation and immune activation in Alzheimer’s disease. J. Neural Transm. (Vienna), 2000, 107(3), 343-353.
[http://dx.doi.org/10.1007/s007020050029] [PMID: 10821443]
Blasko, I.; Knaus, G.; Weiss, E.; Kemmler, G.; Winkler, C.; Falkensammer, G.; Griesmacher, A.; Würzner, R.; Marksteiner, J.; Fuchs, D. Cognitive deterioration in Alzheimer’s disease is accompanied by increase of plasma neopterin. J. Psychiatr. Res., 2007, 41(8), 694-701.
[http://dx.doi.org/10.1016/j.jpsychires.2006.02.001] [PMID: 16542679]
Jacobs, K.R.; Lim, C.K.; Blennow, K.; Zetterberg, H.; Chatterjee, P.; Martins, R.N.; Brew, B.J.; Guillemin, G.J.; Lovejoy, D.B. Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer’s disease and relationship to amyloid-β and tau. Neurobiol. Aging, 2019, 80, 11-20.
[http://dx.doi.org/10.1016/j.neurobiolaging.2019.03.015] [PMID: 31055163]
Westfall, S.; Lomis, N.; Kahouli, I.; Dia, S.Y.; Singh, S.P.; Prakash, S. Microbiome, probiotics and neurodegenerative diseases: deciphering the gut brain axis. Cell. Mol. Life Sci., 2017, 74(20), 3769-3787.
[http://dx.doi.org/10.1007/s00018-017-2550-9] [PMID: 28643167]
Sampson, T.R.; Mazmanian, S.K. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe, 2015, 17(5), 565-576.
[http://dx.doi.org/10.1016/j.chom.2015.04.011] [PMID: 25974299]
Cryan, J.F.; Dinan, T.G. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat. Rev. Neurosci., 2012, 13(10), 701-712.
[http://dx.doi.org/10.1038/nrn3346] [PMID: 22968153]
Sandrini, S.; Aldriwesh, M.; Alruways, M.; Freestone, P. Microbial endocrinology: host-bacteria communication within the gut microbiome. J. Endocrinol., 2015, 225(2), R21-R34.
[http://dx.doi.org/10.1530/JOE-14-0615] [PMID: 25792117]
Gao, K.; Mu, C.L.; Farzi, A.; Zhu, W.Y. Tryptophan metabolism: a link between the gut microbiota and brain. Adv. Nutr., 2019., pii: nmz127
[http://dx.doi.org/10.1093/advances/nmz127] [PMID: 31825083]
Zhao, Y.; Dua, P.; Lukiw, W.J. Microbial sources of amyloid and relevance to amyloidogenesis and Alzheimer’s disease (AD). J. Alzheimers Dis. Parkinsonism, 2015, 5(1), 177.
[PMID: 25977840]
Sharon, G.; Sampson, T.R.; Geschwind, D.H.; Mazmanian, S.K. The central nervous system and the gut microbiome. Cell, 2016, 167(4), 915-932.
[http://dx.doi.org/10.1016/j.cell.2016.10.027] [PMID: 27814521]
Leblhuber, F.; Walli, J.; Demel, U.; Tilz, G.P.; Widner, B.; Fuchs, D. Increased serum neopterin concentrations in patients with Alzheimer’s disease. Clin. Chem. Lab. Med., 1999, 37(4), 429-431.
[http://dx.doi.org/10.1515/CCLM.1999.070] [PMID: 10369114]
Frick, B.; Schroecksnadel, K.; Neurauter, G.; Leblhuber, F.; Fuchs, D. Increasing production of homocysteine and neopterin and degradation of tryptophan with older age. Clin. Biochem., 2004, 37(8), 684-687.
[http://dx.doi.org/10.1016/j.clinbiochem.2004.02.007] [PMID: 15302611]
Franceschi, C.; Bonafè, M.; Valensin, S.; Olivieri, F.; De Luca, M.; Ottaviani, E.; De Benedictis, G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci., 2000, 908, 244-254.
[http://dx.doi.org/10.1111/j.1749-6632.2000.tb06651.x] [PMID: 10911963]
Werner, E.R.; Hirsch-Kauffmann, M.; Fuchs, D.; Hausen, A.; Reibnegger, G.; Schweiger, M.; Wachter, H. Interferon-gamma-induced degradation of tryptophan by human cells in vitro. Biol. Chem. Hoppe Seyler, 1987, 368(10), 1407-1412.
[http://dx.doi.org/10.1515/bchm3.1987.368.2.1407] [PMID: 3122784]
Reibnegger, G.; Huber, L.A.; Jürgens, G.; Schönitzer, D.; Werner, E.R.; Wachter, H.; Wick, G.; Traill, K.N. Approach to define “normal aging” in man. Immune function, serum lipids, lipoproteins and neopterin levels. Mech. Ageing Dev., 1988, 46(1-3), 67-82.
[http://dx.doi.org/10.1016/0047-6374(88)90115-7] [PMID: 3226163]
Murr, C.; Hainz, U.; Asch, E.; Berger, P.; Jenewein, B.; Saurwein-Teissl, M.; Grubeck-Loebenstein, B.; Fuchs, D. Association of increased neopterin production with decreased humoral immunity in the elderly. Exp. Gerontol., 2003, 38(5), 583-587.
[http://dx.doi.org/10.1016/S0531-5565(03)00062-7] [PMID: 12742536]
Leblhuber, F.; Walli, J.; Tilz, G.P.; Demel, U.; Widner, B.; Fuchs, D. Peripheral immune activation in Alzheimer. Pteridines, 2000, 11, 48-53.
Hull, M.; Pasinetti, G.M.; Aisen, P.S. Elevated plasma neopterin levels in Alzheimer disease. Alzheimer Dis. Assoc. Disord., 2000, 14(4), 228-230.
[http://dx.doi.org/10.1097/00002093-200010000-00007] [PMID: 11186601]
Wirleitner, B.; Schroecksnadel, K.; Winkler, C.; Fuchs, D. Neopterin in HIV-1 infection. Mol. Immunol., 2005, 42(2), 183-194.
[http://dx.doi.org/10.1016/j.molimm.2004.06.017] [PMID: 15488607]
Murr, C.; Fuith, L.C.; Widner, B.; Wirleitner, B.; Baier-Bitterlich, G.; Fuchs, D. Increased neopterin concentrations in patients with cancer: indicator of oxidative stress? Anticancer Res., 1999, 19(3A), 1721-1728.
[PMID: 10470106]
Schroecksnadel, K.; Kaser, S.; Ledochowski, M.; Neurauter, G.; Mur, E.; Herold, M.; Fuchs, D. Increased degradation of tryptophan in blood of patients with rheumatoid arthritis. J. Rheumatol., 2003, 30(9), 1935-1939.
[PMID: 12966593]
Schennach, H.; Hessenberger, G.; Mayersbach, P.; Schönitzer, D.; Fuchs, D. Acute cytomegalovirus infections in blood donors are indicated by increased serum neopterin concentrations. Med. Microbiol. Immunol. (Berl.), 2002, 191(2), 115-118.
[http://dx.doi.org/10.1007/s00430-002-0148-8] [PMID: 12410351]
Sastre, M.; Dewachter, I.; Landreth, G.E.; Willson, T.M.; Klockgether, T.; van Leuven, F.; Heneka, M.T. Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J. Neurosci., 2003, 23(30), 9796-9804.
[http://dx.doi.org/10.1523/JNEUROSCI.23-30-09796.2003] [PMID: 14586007]
Blasko, I.; Marx, F.; Steiner, E.; Hartmann, T.; Grubeck-Loebenstein, B. TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. FASEB J., 1999, 13(1), 63-68.
[http://dx.doi.org/10.1096/fasebj.13.1.63] [PMID: 9872930]
Parker, D.C.; Mielke, M.M.; Yu, Q.; Rosenberg, P.B.; Jain, A.; Lyketsos, C.G.; Fedarko, N.S.; Oh, E.S. Plasma neopterin level as a marker of peripheral immune activation in amnestic mild cognitive impairment and Alzheimer’s disease. Int. J. Geriatr. Psychiatry, 2013, 28(2), 149-154.
[http://dx.doi.org/10.1002/gps.3802] [PMID: 22539447]
Strandberg, T.E.; Pitkala, K.H.; Linnavuori, K.; Tilvis, R.S. Cognitive impairment and infectious burden in the elderly. Arch. Gerontol. Geriatr. Suppl., 2004, 38(9), 419-423.
[http://dx.doi.org/10.1016/j.archger.2004.04.053] [PMID: 15207442]
Aiello, A.E.; Hann, M.N.; Kumar, S.; Moore, K.A.; Blythe, L. Novel infectious biomarkers of cognitive impairment. Alzheimers Dement., 2005, 1(1)
de Jong, M.D.; Galasso, G.J.; Gazzard, B.; Griffiths, P.D.; Jabs, D.A.; Kern, E.R.; Spector, S.A. Summary of the ii international symposium on cytomegalovirus. Antiviral Res., 1998, 39(3), 141-162.
[http://dx.doi.org/10.1016/S0166-3542(98)00044-8] [PMID: 9833956]
Zuhair, M.; Smit, G.S.A.; Wallis, G.; Jabbar, F.; Smith, C.; Devleesschauwer, B.; Griffiths, P. Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Rev. Med. Virol., 2019, 29(3), e2034
[http://dx.doi.org/10.1002/rmv.2034] [PMID: 30706584]
Renvoize, E.B.; Hambling, M.H. Cytomegalovirus infection and Alzheimer’s disease. Age Ageing, 1984, 13(4), 205-209.
[http://dx.doi.org/10.1093/ageing/13.4.205] [PMID: 6089524]
Lin, W.R.; Wozniak, M.A.; Cooper, R.J.; Wilcock, G.K.; Itzhaki, R.F. Herpesviruses in brain and Alzheimer’s disease. J. Pathol., 2002, 197(3), 395-402.
[http://dx.doi.org/10.1002/path.1127] [PMID: 12115887]
Lövheim, H.; Olsson, J.; Weidung, B.; Johansson, A.; Eriksson, S.; Hallmans, G.; Elgh, F. Interaction between cytomegalovirus and herpes simplex virus type 1 associated with the risk of alzheimer’s disease development. J. Alzheimers Dis., 2018, 61(3), 939-945.
[http://dx.doi.org/10.3233/JAD-161305] [PMID: 29254081]
Barnes, L.L.; Capuano, A.W.; Aiello, A.E.; Turner, A.D.; Yolken, R.H.; Torrey, E.F.; Bennett, D.A. Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals. J. Infect. Dis., 2015, 211(2), 230-237.
[http://dx.doi.org/10.1093/infdis/jiu437] [PMID: 25108028]
Westman, G.; Berglund, D.; Widén, J.; Ingelsson, M.; Korsgren, O.; Lannfelt, L.; Sehlin, D.; Lidehall, A.K.; Eriksson, B.M. Increased inflammatory response in cytomegalovirus seropositive patients with Alzheimer’s disease. PLoS One, 2014, 9(5), e96779
[http://dx.doi.org/10.1371/journal.pone.0096779] [PMID: 24804776]
Gabin, J.M.; Saltvedt, I.; Tambs, K.; Holmen, J. The association of high sensitivity C-reactive protein and incident Alzheimer disease in patients 60 years and older: The HUNT study, Norway. Immun. Ageing, 2018, 15, 4.
[http://dx.doi.org/10.1186/s12979-017-0106-3] [PMID: 29387136]
Richartz, E.; Stransky, E.; Batra, A.; Simon, P.; Lewczuk, P.; Buchkremer, G.; Bartels, M.; Schott, K. Decline of immune responsiveness: a pathogenetic factor in Alzheimer’s disease? J. Psychiatr. Res., 2005, 39(5), 535-543.
[http://dx.doi.org/10.1016/j.jpsychires.2004.12.005] [PMID: 15992563]
Singh, V.K.; Guthikonda, P. Circulating cytokines in Alzheimer’s disease. J. Psychiatr. Res., 1997, 31(6), 657-660.
[http://dx.doi.org/10.1016/S0022-3956(97)00023-X] [PMID: 9447570]
Lombardi, V.R.M.; García, M.; Rey, L.; Cacabelos, R. Characterization of cytokine production, screening of lymphocyte subset patterns and in vitro apoptosis in healthy and Alzheimer’s Disease (AD) individuals. J. Neuroimmunol., 1999, 97(1-2), 163-171.
[http://dx.doi.org/10.1016/S0165-5728(99)00046-6] [PMID: 10408971]
De Luigi, A.; Fragiacomo, C.; Lucca, U.; Quadri, P.; Tettamanti, M.; Grazia De Simoni, M. Inflammatory markers in Alzheimer’s disease and multi-infarct dementia. Mech. Ageing Dev., 2001, 122(16), 1985-1995.
[http://dx.doi.org/10.1016/S0047-6374(01)00313-X] [PMID: 11589916]
Paganelli, R.; Di Iorio, A.; Patricelli, L.; Ripani, F.; Sparvieri, E.; Faricelli, R.; Iarlori, C.; Porreca, E.; Di Gioacchino, M.; Abate, G. Proinflammatory cytokines in sera of elderly patients with dementia: levels in vascular injury are higher than those of mild-moderate Alzheimer’s disease patients. Exp. Gerontol., 2002, 37(2-3), 257-263.
[http://dx.doi.org/10.1016/S0531-5565(01)00191-7] [PMID: 11772511]
Stein, P.S.; Desrosiers, M.; Donegan, S.J.; Yepes, J.F.; Kryscio, R.J. Tooth loss, dementia and neuropathology in the Nun study. J. Am. Dent. Assoc., 2007, 138(10), 1314-1322.
[http://dx.doi.org/10.14219/jada.archive.2007.0046] [PMID: 17908844]
Pritchard, A.B.; Crean, S.; Olsen, I.; Singhrao, S.K. Periodontitis, microbes and their role in Alzheimer’s disease. Front. Aging Neurosci., 2017, 9, 336.
[http://dx.doi.org/10.3389/fnagi.2017.00336] [PMID: 29114218]
Leblhuber, F.; Strasser, B.; Steiner, K.; Gostner, J.; Schuetz, B.; Fuchs, D. On the role of intestinal microbiota in patients with cognitive decline J. Pharm. Pharmacol, (David Publishing), 2017, 5, 648-53.
Wu, Z.; Nakanishi, H. Connection between periodontitis and Alzheimer’s disease: possible roles of microglia and leptomeningeal cells. J. Pharmacol. Sci., 2014, 126(1), 8-13.
[http://dx.doi.org/10.1254/jphs.14R11CP] [PMID: 25168594]
Kamer, A.R.; Pirraglia, E.; Tsui, W.; Rusinek, H.; Vallabhajosula, S.; Mosconi, L.; Yi, L.; McHugh, P.; Craig, R.G.; Svetcov, S.; Linker, R.; Shi, C.; Glodzik, L.; Williams, S.; Corby, P.; Saxena, D.; de Leon, M.J. Periodontal disease associates with higher brain amyloid load in normal elderly. Neurobiol. Aging, 2015, 36(2), 627-633.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.038] [PMID: 25491073]
Shoemark, D.K.; Allen, S.J. The microbiome and disease: reviewing the links between the oral microbiome, aging, and Alzheimer’s disease. J. Alzheimers Dis., 2015, 43(3), 725-738.
[http://dx.doi.org/10.3233/JAD-141170] [PMID: 25125469]
Sochocka, M.; Sobczyński, M.; Sender-Janeczek, A.; Zwolińska, K.; Błachowicz, O.; Tomczyk, T.; Ziętek, M.; Leszek, J. Association between periodontal health status and cognitive abilities. The role of cytokine profile and systemic inflammation. Curr. Alzheimer Res., 2017, 14(9), 978-990.
[http://dx.doi.org/10.2174/1567205014666170316163340] [PMID: 28317488]
Wadhawan, A.; Reynolds, M.A.; Makkar, H.; Scott, A.J.; Potocki, E.; Hoisington, A.J.; Brenner, L.A.; Dagdag, A.; Lowry, C.A.; Dwivedi, Y.; Postolache, T.T. Periodontal pathogens and neuropsychiatric health. Curr. Top. Med. Chem., 2020. [ePub ahead of Print]
[PMID: 31924157]
Arimatsu, K.; Yamada, H.; Miyazawa, H.; Minagawa, T.; Nakajima, M.; Ryder, M.I.; Gotoh, K.; Motooka, D.; Nakamura, S.; Iida, T.; Yamazaki, K. Oral pathobiont induces systemic inflammation and metabolic changes associated with alteration of gut microbiota. Sci. Rep., 2014, 4, 4828.
[http://dx.doi.org/10.1038/srep04828] [PMID: 24797416]
Bodet, C.; Chandad, F.; Grenier, D. [Pathogenic potential of Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, the red bacterial complex associated with periodontitis]. Pathol. Biol. (Paris), 2007, 55(3-4), 154-162.
[http://dx.doi.org/10.1016/j.patbio.2006.07.045] [PMID: 17049750]
Leblhuber, F.; Huemer, J.; Steiner, K.; Gostner, J.M.; Fuchs, D. Knock-on effect of periodontitis to the pathogenesis of Alzheimer’s disease? Wien. Klin. Wochenschr., 2020.
[http://dx.doi.org/10.1007/s00508-020-01638-5] [PMID: 32215721]
Olsen, I.; Taubman, M.A.; Singhrao, S.K. Porphyromonas gingivalis suppresses adaptive immunity in periodontitis, atherosclerosis, and Alzheimer’s disease. J. Oral Microbiol., 2016, 8, 33029.
[http://dx.doi.org/10.3402/jom.v8.33029] [PMID: 27882863]
Leblhuber, F.; Steiner, K.; Schuetz, B.; Fuchs, D.; Gostner, J.M. Probiotic supplementation in patients with alzheimer’s dementia - an explorative intervention study. Curr. Alzheimer Res., 2018, 15(12), 1106-1113.
[http://dx.doi.org/10.2174/1389200219666180813144834] [PMID: 30101706]
Reid, G. Probiotics: definition, scope and mechanisms of action. Best Pract. Res. Clin. Gastroenterol., 2016, 30(1), 17-25.
[http://dx.doi.org/10.1016/j.bpg.2015.12.001] [PMID: 27048893]
Jackson, M.A.; Jeffery, I.B.; Beaumont, M.; Bell, J.T.; Clark, A.G.; Ley, R.E.; O’Toole, P.W.; Spector, T.D.; Steves, C.J. Signatures of early frailty in the gut microbiota. Genome Med., 2016, 8(1), 8.
[http://dx.doi.org/10.1186/s13073-016-0262-7] [PMID: 26822992]
Leblhuber, F.; Geisler, S.; Steiner, K.; Fuchs, D.; Schütz, B. Elevated fecal calprotectin in patients with Alzheimer’s dementia indicates leaky gut. J. Neural Transm. (Vienna), 2015, 122(9), 1319-1322.
[http://dx.doi.org/10.1007/s00702-015-1381-9] [PMID: 25680441]
Giil, L.M.; Midttun, Ø.; Refsum, H.; Ulvik, A.; Advani, R.; Smith, A.D.; Ueland, P.M. Kynurenine pathway metabolites in Alzheimer’s disease. J. Alzheimers Dis., 2017, 60(2), 495-504.
[http://dx.doi.org/10.3233/JAD-170485] [PMID: 28869479]
van Beek, A.A.; Hugenholtz, F.; Meijer, B.; Sovran, B.; Perdijk, O.; Vermeij, W.P.; Brandt, R.M.; Barnhoorn, S.; Hoeijmakers, J.H.; de Vos, P.; Leenen, P.J.; Hendriks, R.W.; Savelkoul, H.F. Frontline Science: Tryptophan restriction arrests B cell development and enhances microbial diversity in WT and prematurely aging Ercc1-/Δ7 mice. J. Leukoc. Biol., 2017, 101(4), 811-821.
[http://dx.doi.org/10.1189/jlb.1HI0216-062RR] [PMID: 27418353]
Lehrer, S. Nasal NSAIDs for Alzheimer’s disease. Am. J. Alzheimers Dis. Other Demen., 2014, 29(5), 401-403.
[http://dx.doi.org/10.1177/1533317513518658] [PMID: 24413537]
Brendel, M.; Sauerbeck, J.; Greven, S.; Kotz, S.; Scheiwein, F.; Blautzik, J.; Delker, A.; Pogarell, O.; Ishii, K.; Bartenstein, P.; Rominger, A. Alzheimer’s Disease Neuroimaging Initiative. Serotonin selective reuptake inhibitor treatment improves cognition and grey matter atrophy but not amyloid burden during two year follow up in mild cognitive impairment and Alzheimer’s disease patients with depressive symptoms. J. Alzheimers Dis., 2018, 65(3), 793-806.
[http://dx.doi.org/10.3233/JAD-170387] [PMID: 30010116]
Ashford, J.W. Treatment of Alzheimer’s disease: Trazodone, sleep, serotonin, norepinephri-ne, and future directions. J. Alzheimers Dis., 2019, 67(3), 923-930.
[http://dx.doi.org/10.3233/JAD-181106] [PMID: 30776014]
Novak, P.; Schmidt, R.; Kontsekova, E.; Kovacech, B.; Smolek, T.; Katina, S.; Fialova, L.; Prcina, M.; Parrak, V.; Dal-Bianco, P.; Brunner, M.; Staffen, W.; Rainer, M.; Ondrus, M.; Ropele, S.; Smisek, M.; Sivak, R.; Zilka, N.; Winblad, B.; Novak, M. FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer’s disease. Alzheimers Res. Ther., 2018, 10(1), 108.
[http://dx.doi.org/10.1186/s13195-018-0436-1] [PMID: 30355322]
McGeer, P.L.; McGeer, E.G. Inflammation, autotoxicity and Alzheimer disease. Neurobiol. Aging, 2001, 22(6), 799-809.
[http://dx.doi.org/10.1016/S0197-4580(01)00289-5] [PMID: 11754986]
Mrak, R.E.; Griffin, W.S. Glia and their cytokines in progression of neurodegeneration. Neurobiol. Aging, 2005, 26(3), 349-354.
[http://dx.doi.org/10.1016/j.neurobiolaging.2004.05.010] [PMID: 15639313]
Murakami, Y.; Kawata, A.; Ito, S.; Katayama, T.; Fujisawa, S. The radical scavenging activity and cytotoxicity of resveratrol, orcinol and 4-allylphenol and their inhibitory effect on cox-2 gene expression and Nf-kappa B activation in RAW264.7 cells stimulated with Porphyromonas gingivalis fimbriae. In Vivo, 2015, 29(3), 341-349.
[PMID: 25977379]
Dominy, S.S.; Lynch, C.; Ermini, F.; Benedyk, M.; Marczyk, A.; Konradi, A.; Nguyen, M.; Haditsch, U.; Raha, D.; Griffin, C.; Holsinger, L.J.; Arastu-Kapur, S.; Kaba, S.; Lee, A.; Ryder, M.I.; Potempa, B.; Mydel, P.; Hellvard, A.; Adamowicz, K.; Hasturk, H.; Walker, G.D.; Reynolds, E.C.; Faull, R.L.M.; Curtis, M.A.; Dragunow, M.; Potempa, J. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci. Adv., 2019, 5(1), 3333
[http://dx.doi.org/10.1126/sciadv.aau3333] [PMID: 30746447]
Sun, J.; Xu, J.; Ling, Y.; Wang, F.; Gong, T.; Yang, C.; Ye, S.; Ye, K.; Wei, D.; Song, Z.; Chen, D.; Liu, J. Fecal microbiota transplantation alleviated Alzheimer’s disease-like pathogenesis in APP/PS1 transgenic mice. Transl. Psychiatry, 2019, 9(1), 189.
[http://dx.doi.org/10.1038/s41398-019-0525-3] [PMID: 31383855]
Caracciolo, B.; Xu, W.; Collins, S.; Fratiglioni, L. Cognitive decline, dietary factors and gut-brain interactions. Mech. Ageing Dev., 2014, 136-137, 59-69.
[http://dx.doi.org/10.1016/j.mad.2013.11.011] [PMID: 24333791]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [1415 - 1421]
Pages: 7
DOI: 10.2174/1568026620666200514090359
Price: $65

Article Metrics

PDF: 18