Active Amyloid-β Vaccination Results in Epigenetic Changes in the Hippocampus of an Alzheimer’s Disease-Like Mouse Model

Author(s): Roy Lardenoije, Daniël L.A. van den Hove, Sophie E. Jung, Monique Havermans, Peter Blackburn, Bin Liu, Bart P.F. Rutten, Cynthia A. Lemere*.

Journal Name: Current Alzheimer Research

Volume 16 , Issue 9 , 2019

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Abstract:

Background: While evidence accumulates for a role of epigenetic modifications in the pathophysiological cascade of Alzheimer’s disease (AD), amyloid-β (Aβ)-targeted active immunotherapy approaches are under investigation to prevent or slow the progression of AD. The impact of Aβ active vaccines on epigenetic markers has not been studied thus far.

Objective: The current study aims to establish the relationship between active immunotherapy with a MER5101-based vaccine (consisting of Aβ1-15 copies conjugated with a 7 aa spacer to the diphtheria toxoid carrier protein, formulated in a Th2-biased adjuvant) and epigenetic DNA modifications in the hippocampus of APPswe/PS1dE9 mice.

Methods: As we previously reported, immunotherapy started when the mice were 10 months of age and behavioral testing occurred at 14 months of age, after which the mice were sacrificed for further analysis of their brains. In this add-on study, global levels of DNA methylation and hydroxymethylation, and DNA methyltransferase 3A (DNMT3A) were determined using quantitative immunohistochemistry, and compared to our previously analyzed immunization-induced changes in AD-related neuropathology and cognition.

Results: Active immunization did not affect global DNA methylation levels but instead, resulted in decreased DNA hydroxymethylation and DNMT3A levels. Independent of immunization, inverse correlations with behavioral performance were observed for levels of DNA methylation and hydroxymethylation, as well as DNMT3A, while Aβ pathology and synaptic markers did not correlate with DNA methylation levels but did positively correlate with DNA hydroxymethylation and levels of DNMT3A.

Conclusion: Our results indicate that active Aβ vaccination has significant effects on the epigenome in the hippocampus of APPswe/PS1dE9 mice, and suggest that DNA methylation and hydroxymethylation may be involved in cognitive functioning.

Keywords: Alzheimer’s disease, amyloid-β, active vaccine, epigenetics, DNA methylation, mouse model.

[1]
Agadjanyan MG, Petrovsky N, Ghochikyan A. A fresh perspective from immunologists and vaccine researchers: active vaccination strategies to prevent and reverse Alzheimer’s disease. Alzheimers Dement 11(10): 1246-59. (2015).
[http://dx.doi.org/10.1016/j.jalz.2015.06.1884] [PMID: 26192465]
[2]
Bittar A, Sengupta U, Kayed R. Prospects for strain-specific immunotherapy in Alzheimer’s disease and tauopathies. NPJ Vaccines 3(1): 9. (2018).
[http://dx.doi.org/10.1038/s41541-018-0046-8] [PMID: 29507776]
[3]
Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64(9): 1553-62. (2005).
[http://dx.doi.org/10.1212/01.WNL.0000159740.16984.3C] [PMID: 15883316]
[4]
Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, et al. Long-term follow-up of patients immunized with AN1792: reduced functional decline in antibody responders. Curr Alzheimer Res 6(2): 144-51. (2009).
[http://dx.doi.org/10.2174/156720509787602852] [PMID: 19355849]
[5]
Farlow MR, Andreasen N, Riviere M-E, Vostiar I, Vitaliti A, Sovago J, et al. Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease. Alzheimers Res Ther 7(1): 23. (2015).
[http://dx.doi.org/10.1186/s13195-015-0108-3] [PMID: 25918556]
[6]
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400(6740): 173-7. (1999).
[http://dx.doi.org/10.1038/22124] [PMID: 10408445]
[7]
Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, et al. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann Neurol 48(4): 567-79. (2000).
[http://dx.doi.org/10.1002/1531-8249(200010)48:4<567:AID-ANA3>3.0.CO;2-W] [PMID: 11026440]
[8]
Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Desai R, et al. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease. Ann Neurol 48(4): 567-79. (2000).
[9]
Lemere CA, Spooner ET, Leverone JF, Mori C, Clements JD. Intranasal immunotherapy for the treatment of Alzheimer’s disease: Escherichia coli LT and LT(R192G) as mucosal adjuvants. Neurobiol Aging 23(6): 991-1000. (2002).
[http://dx.doi.org/10.1016/S0197-4580(02)00127-6] [PMID: 12470794]
[10]
Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 408(6815): 979-82. (2000).
[http://dx.doi.org/10.1038/35050110] [PMID: 11140685]
[11]
Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408(6815): 982-5. (2000).
[http://dx.doi.org/10.1038/35050116] [PMID: 11140686]
[12]
Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR, Jenkins L, et al. Evaluation of the safety and immunogenicity of synthetic Abeta42 (AN1792) in patients with AD. Neurology 64(1): 94-101. (2005).
[http://dx.doi.org/10.1212/01.WNL.0000148604.77591.67] [PMID: 15642910]
[13]
Cerasoli E, Ryadnov MG, Austen BM. The elusive nature and diagnostics of misfolded Aβ oligomers. Front Chem 3: 17. (2015).
[http://dx.doi.org/10.3389/fchem.2015.00017] [PMID: 25853119]
[14]
Choudhuri S. From Waddington’s epigenetic landscape to small noncoding RNA: some important milestones in the history of epigenetics research. Toxicol Mech Methods 21(4): 252-74. (2011).
[http://dx.doi.org/10.3109/15376516.2011.559695] [PMID: 21495865]
[15]
Liu L, Li Y, Tollefsbol TO. Gene-environment interactions and epigenetic basis of human diseases. Curr Issues Mol Biol 10(1-2): 25-36. (2008).
[PMID: 18525104]
[16]
Lardenoije R, Iatrou A, Kenis G, Kompotis K, Steinbusch HW, Mastroeni D, et al. The epigenetics of aging and neurodegeneration. Prog Neurobiol 131: 21-64. (2015).
[http://dx.doi.org/10.1016/j.pneurobio.2015.05.002] [PMID: 26072273]
[17]
Globisch D, Münzel M, Müller M, Michalakis S, Wagner M, Koch S, et al. Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS One 5(12)e15367 (2010).
[http://dx.doi.org/10.1371/journal.pone.0015367] [PMID: 21203455]
[18]
Kriaucionis S, Heintz N. The nuclear DNA base 5- hydroxymethylcytosine is present in Purkinje neurons and the brain. Science (80- ) 324(5929): 929-30. (2009).
[19]
Chouliaras L, Mastroeni D, Delvaux E, Grover A, Kenis G, Hof PR, et al. Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients. Neurobiol Aging 2013; 34(9): 2091-9.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.02.021] [PMID: 23582657]
[20]
Condliffe D, Wong A, Troakes C, Proitsi P, Patel Y, Chouliaras L, et al. Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer’s disease brain. Neurobiol Aging 35(8): 1850-4. (2014).
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.02.002] [PMID: 24679604]
[21]
Chen K-L, Wang SS-S, Yang Y-Y, Yuan R-Y, Chen R-M, Hu C-J. The epigenetic effects of amyloid-beta(1-40) on global DNA and neprilysin genes in murine cerebral endothelial cells. Biochem Biophys Res Commun 378(1): 57-61. (2009).
[http://dx.doi.org/10.1016/j.bbrc.2008.10.173] [PMID: 19007750]
[22]
Lardenoije R, Pishva E, Lunnon K, van den Hove DL. Neuroepigenetics of aging and age-related neurodegenerative disorders. Prog Mol Biol Transl Sci 158: 49-82. (2018).
[http://dx.doi.org/10.1016/bs.pmbts.2018.04.008]
[23]
Dogra P, Ghoneim HE, Abdelsamed HA, Youngblood B. Generating long-lived CD8(+) T-cell memory: Insights from epigenetic programs. Eur J Immunol 46(7): 1548-62. (2016).
[http://dx.doi.org/10.1002/eji.201545550] [PMID: 27230488]
[24]
Uthayakumar D, Paris S, Chapat L, Freyburger L, Poulet H, De Luca K. Non-specific effects of vaccines illustrated through the BCG example: from observations to demonstrations. Front Immunol 9: 2869. (2018).
[http://dx.doi.org/10.3389/fimmu.2018.02869] [PMID: 30564249]
[25]
Janjanam VD, Mukherjee N, Lockett GA, Rezwan FI. Kurukulaaratchy R5, Mitchell F, et al. Tetanus vaccination is associated with differential DNA-methylation: reduces the risk of asthma in adolescence. Vaccine 34(51): 6493-501. (2016).
[http://dx.doi.org/10.1016/j.vaccine.2016.10.068] [PMID: 27866770]
[26]
Zimmermann MT, Oberg AL, Grill DE, Ovsyannikova IG, Haralambieva IH, Kennedy RB, et al. System-wide associations between DNA-methylation, gene expression, and humoral immune response to influenza vaccination. PLoS One 11(3)e0152034 (2016).
[http://dx.doi.org/10.1371/journal.pone.0152034] [PMID: 27031986]
[27]
Pezeshki A, Ovsyannikova IG, McKinney BA, Poland GA, Kennedy RB. The role of systems biology approaches in determining molecular signatures for the development of more effective vaccines. Expert Rev Vaccines 18(3): 253-67. (2019).
[http://dx.doi.org/10.1080/14760584.2019.1575208] [PMID: 30700167]
[28]
Liu B, Frost JL, Sun J, Fu H, Grimes S, Blackburn P, et al. MER5101, a novel Aβ1-15: DT conjugate vaccine, generates a robust anti-Aβ antibody response and attenuates Aβ pathology and cognitive deficits in APPswe/PS1ΔE9 transgenic mice. J Neurosci 33(16): 7027-37. (2013).
[http://dx.doi.org/10.1523/JNEUROSCI.5924-12.2013] [PMID: 23595760]
[29]
Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, et al. Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: Evidence for augmentation of a 42-specific γ secretase. Hum Mol Genet 13(2): 159-70. (2004).
[30]
Maier M, Seabrook TJ, Lemere CA. Modulation of the humoral and cellular immune response in Abeta immunotherapy by the adjuvants monophosphoryl lipid A (MPL), cholera toxin B subunit (CTB) and E. coli enterotoxin LT(R192G). Vaccine 23(44): 5149-59. (2005).
[http://dx.doi.org/10.1016/j.vaccine.2005.06.018] [PMID: 16054274]
[31]
Frost JL, Liu B, Rahfeld J-U, Kleinschmidt M, O’Nuallain B, Le KX, et al. An anti-pyroglutamate-3 Aβ vaccine reduces plaques and improves cognition in APPswe/PS1ΔE9 mice. Neurobiol Aging 36(12): 3187-99. (2015).
[http://dx.doi.org/10.1016/j.neurobiolaging.2015.08.021] [PMID: 26453001]
[32]
Wang J, Gong B, Zhao W, Tang C, Varghese M, Nguyen T, et al. Epigenetic mechanisms linking diabetes and synaptic impairments. Diabetes 63(2): 645-54. (2014).
[http://dx.doi.org/10.2337/db13-1063] [PMID: 24154559]
[33]
Rao JS, Keleshian VL, Klein S, Rapoport SI. Epigenetic modifications in frontal cortex from Alzheimer’s disease and bipolar disorder patients. Transl Psychiatry 2e132 (2012).
[http://dx.doi.org/10.1038/tp.2012.55] [PMID: 22760556]
[34]
Bustos FJ, Ampuero E, Jury N, Aguilar R, Falahi F, Toledo J, et al. Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer’s disease mice. Brain 140(12): 3252-68. (2017).
[http://dx.doi.org/10.1093/brain/awx272] [PMID: 29155979]
[35]
Coppieters N, Dieriks BV, Lill C, Faull RL, Curtis MA, Dragunow M. Global changes in DNA methylation and hydroxymethylation in Alzheimer’s disease human brain. Neurobiol Aging 35(6): 1334-44. (2014).
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.11.031] [PMID: 24387984]
[36]
Lardenoije R, van den Hove DLA, Havermans M, van Casteren A, Le KX, Palmour R, et al. Age-related epigenetic changes in hippocampal subregions of four animal models of Alzheimer’s disease. Mol Cell Neurosci 86: 1-15. (2018).
[http://dx.doi.org/10.1016/j.mcn.2017.11.002] [PMID: 29113959]
[37]
Amouroux R, Nashun B, Shirane K, Nakagawa S, Hill PW, D’Souza Z, et al. De novo DNA methylation drives 5hmC accumulation in mouse zygotes. Nat Cell Biol 18(2): 225-33. (2016).
[http://dx.doi.org/10.1038/ncb3296] [PMID: 26751286]
[38]
Chen C-C, Wang K-Y, Shen C-KJ. DNA 5-methylcytosine demethylation activities of the mammalian DNA methyltransferases. J Biol Chem 288(13): 9084-91. (2013).
[http://dx.doi.org/10.1074/jbc.M112.445585] [PMID: 23393137]


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VOLUME: 16
ISSUE: 9
Year: 2019
Page: [861 - 870]
Pages: 10
DOI: 10.2174/1567205016666190827122009
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