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Maternal choline supplementation ameliorates Alzheimer’s disease pathology by reducing brain homocysteine levels across multiple generations

Molecular Psychiatry volume 25, pages 2620–2629 (2020)Cite this article

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Abstract

The lack of effective treatments for Alzheimer’s disease (AD) is alarming, considering the number of people currently affected by this disorder and the projected increase over the next few decades. Elevated homocysteine (Hcy) levels double the risk of developing AD. Choline, a primary dietary source of methyl groups, converts Hcy to methionine and reduces age-dependent cognitive decline. Here, we tested the transgenerational benefits of maternal choline supplementation (ChS; 5.0 g/kg choline chloride) in two generations (Gen) of APP/PS1 mice. We first exposed 2.5-month-old mice to the ChS diet and allowed them to breed with each other to generate Gen-1 mice. Gen-1 mice were exposed to the ChS diet only during gestation and lactation; once weaned at postnatal day 21, Gen-1 mice were then kept on the control diet for the remainder of their life. We also bred a subset of Gen-1 mice to each other and obtained Gen-2 mice; these mice were never exposed to ChS. We found that ChS reduced Aβ load and microglia activation, and improved cognitive deficits in old Gen-1 and Gen-2 APP/PS1 mice. Mechanistically, these changes were linked to a reduction in brain Hcy levels in both generations. Further, RNA-Seq data from APP/PS1 hippocampal tissue revealed that ChS significantly changed the expression of 27 genes. These genes were enriched for inflammation, histone modifications, and neuronal death functional classes. Our results are the first to demonstrate a transgenerational benefit of ChS and suggest that modifying the maternal diet with additional choline reduces AD pathology across multiple generations.

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References

  1. Association Association. 2018 Alzheimer’s Association disease facts and figures. Alzheimer’s Demen. 2018;14:367–429.

    Google Scholar 

  2. Dosunmu R, Wu J, Basha MR, Zawia NH. Environmental and dietary risk factors in Alzheimer’s disease. Expert Rev Neurother. 2007;7:887–900.

    CAS  PubMed  Google Scholar 

  3. Hu N, Yu JT, Tan L, Wang YL, Sun L, Tan L. Nutrition and the risk of Alzheimer’s disease. Biomed Res Int. 2013;2013:524820.

    PubMed  PubMed Central  Google Scholar 

  4. Morris MC, Tangney CC, Wang Y, Sacks FM, Bennett DA, Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimer’s Dement. 2015;11:1007–14.

    Google Scholar 

  5. Berti V, Walters M, Sterling J, Quinn CG, Logue M, Andrews R, et al. Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults. Neurology. 2018;90:e1789–e98.

    PubMed  PubMed Central  Google Scholar 

  6. Li J-G, Chu J, Barrero C, Merali S, Praticó D. Homocysteine exacerbates β-amyloid pathology, tau pathology, and cognitive deficit in a mouse model of alzheimer disease with plaques and tangles. Ann Neurol. 2014;75:851–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Morris MS. Homocysteine and Alzheimer’s disease. Lancet Neurol. 2003;2:425–28.

    CAS  PubMed  Google Scholar 

  8. Isobe C, Murata T, Sato C, Terayama Y. Increase of total homocysteine concentration in cerebrospinal fluid in patients with Alzheimer’s disease and Parkinson’s disease. Life Sci. 2005;77:1836–43.

    CAS  PubMed  Google Scholar 

  9. Shen L, Ji H-F. Associations between homocysteine, folic acid, vitamin B12 and Alzheimer’s disease: insights from meta-analyses. J Alzheimer’s Dis. 2015;46:777–90.

    CAS  Google Scholar 

  10. Whalley LJ, Duthie SJ, Collins AR, Starr JM, Deary IJ, Lemmon H, et al. Homocysteine, antioxidant micronutrients and late onset dementia. Eur J Nutr. 2014;53:277–85.

    CAS  PubMed  Google Scholar 

  11. Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett. 2006;580:2994–3005.

    CAS  PubMed  Google Scholar 

  12. Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D, Rogers E, et al. Homocysteine potentiates β-amyloid neurotoxicity: role of oxidative stress. J Neurochem. 2001;78:249–53.

    CAS  PubMed  Google Scholar 

  13. Zhuo J-M, Portugal GS, Kruger WD, Wang H, Gould TJ, Pratico D. Diet-induced hyperhomocysteinemia increases amyloid-beta formation and deposition in a mouse model of Alzheimer’s disease. Curr Alzheimer Res. 2010;7:140–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Pacheco-Quinto J, Rodriguez de Turco EB, DeRosa S, Howard A, Cruz-Sanchez F, Sambamurti K, et al. Hyperhomocysteinemic Alzheimer’s mouse model of amyloidosis shows increased brain amyloid beta peptide levels. Neurobiol Dis. 2006;22:651–56.

    CAS  PubMed  Google Scholar 

  15. Olthof M, J Brink E, B Katan M, Verhoef P. Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. Am J Clin Nutr. 2005,82:111–17.

  16. Steenge GR, Verhoef P, Katan MB. Betaine supplementation lowers plasma homocysteine in healthy men and women. J Nutr. 2003;133:1291–95.

    CAS  PubMed  Google Scholar 

  17. Ash JA, Velazquez R, Kelley CM, Powers BE, Ginsberg SD, Mufson EJ, et al. Maternal choline supplementation improves spatial mapping and increases basal forebrain cholinergic neuron number and size in aged Ts65Dn mice. Neurobiol Dis. 2014;70:32–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Powers BE, Kelley CM, Velazquez R, Ash JA, Strawderman MS, Alldred MJ, et al. Maternal choline supplementation in a mouse model of Down syndrome: effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring. Neuroscience. 2017;340:501–14.

    CAS  PubMed  Google Scholar 

  19. Velazquez R, Ash JA, Powers BE, Kelley CM, Strawderman M, Luscher ZI, et al. Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis. 2013;58:92–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23:5293–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Waterland RA, Travisano M, Tahiliani KG, Rached MT, Mirza S. Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes (Lond). 2008;32:1373–79.

    CAS  Google Scholar 

  22. Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet. 2004;13:159–70.

    CAS  PubMed  Google Scholar 

  23. Caccamo A, Ferreira E, Branca C, Oddo S. p62 improves AD-like pathology by increasing autophagy. Mol Psychiatry. 2017;22:865–73.

    CAS  PubMed  Google Scholar 

  24. Velazquez R, Ferreira E, Tran A, Turner EC, Belfiore R, Branca C et al. Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits. Aging Cell 2018;17:e12775.

  25. Velazquez R, Tran A, Ishimwe E, Denner L, Dave N, Oddo S, et al. Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer’s disease. Neurobiol Aging. 2017;58:1–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Velazquez R, Shaw DM, Caccamo A, Oddo S. Pim1 inhibition as a novel therapeutic strategy for Alzheimer’s disease. Mol. Neurodegener. 2016;11:52.

  27. Ueland PM, Helland S, Broch OJ, Schanche JS. Homocysteine in tissues of the mouse and rat. J Biol Chem. 1984;259:2360–64.

    CAS  PubMed  Google Scholar 

  28. Holm PI, Ueland PM, Kvalheim G, Lien EA. Determination of choline, betaine, and dimethylglycine in plasma by a high-throughput method based on normal-phase chromatography-tandem mass spectrometry. Clin Chem. 2003;49:286–94.

    CAS  PubMed  Google Scholar 

  29. Dobin SM, Malone VS, Lopez L, Donner LR. Unusual histologic variant of a low-grade fibromyxoid sarcoma in a 3-year-old boy with complex chromosomal translocations involving 7q34, 10q11.2, and 16p11.2 and rearrangement of the FUS gene. Pediatr Dev Pathol. 2013;16:86–90.

    PubMed  Google Scholar 

  30. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    PubMed  PubMed Central  Google Scholar 

  31. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28:27–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Mi H, Poudel S, Muruganujan A, Casagrande JT, Thomas PD. PANTHER version 10: expanded protein families and functions, and analysis tools. Nucleic Acids Res. 2016;44:D336–42.

    CAS  PubMed  Google Scholar 

  33. Fabregat A, Sidiropoulos K, Garapati P, Gillespie M, Hausmann K, Haw R, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2016;44):D481–87.

    CAS  PubMed  Google Scholar 

  34. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Chatr-Aryamontri A, Oughtred R, Boucher L, Rust J, Chang C, Kolas NK, et al. The BioGRID interaction database: 2017 update. Nucleic Acids Res. 2017;45:D369–D79.

    CAS  PubMed  Google Scholar 

  36. Benjamini YaH Yosef. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc. 1995;57:289–300.

    Google Scholar 

  37. Wang J, Duncan D, Shi Z, Zhang B. WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res. 2013;41:W77–83.

    PubMed  PubMed Central  Google Scholar 

  38. Mellott TJ, Huleatt OM, Shade BN, Pender SM, Liu YB, Slack BE, et al. Perinatal choline supplementation reduces amyloidosis and increases choline acetyltransferase expression in the hippocampus of theAPPswePS1dE9 alzheimer’s disease model mice. PLoS ONE. 2017;12:e0170450.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zotova E, Holmes C, Johnston D, Neal JW, Nicoll JA, Boche D. Microglial alterations in human Alzheimer’s disease following Abeta42 immunization. Neuropathol Appl Neurobiol. 2011;37:513–24.

    CAS  PubMed  Google Scholar 

  40. Oikonomidi A, Lewczuk P, Kornhuber J, Smulders Y, Linnebank M, Semmler A, et al. Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta. J Neurochem. 2016;139:324–32.

    CAS  PubMed  Google Scholar 

  41. Agnati LF, Genedani S, Leo G, Forni A, Woods AS, Filaferro M, et al. Abeta peptides as one of the crucial volume transmission signals in the trophic units and their interactions with homocysteine. Physiological implications and relevance for Alzheimer’s disease. J Neural Transm (Vienna). 2007;114:21–31.

    CAS  Google Scholar 

  42. Li JG, Chu J, Barrero C, Merali S, Pratico D. Homocysteine exacerbates beta-amyloid pathology, tau pathology, and cognitive deficit in a mouse model of Alzheimer disease with plaques and tangles. Ann Neurol. 2014;75:851–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ho PI, Collins SC, Dhitavat S, Ortiz D, Ashline D, Rogers E, et al. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem. 2001;78:249–53.

    CAS  PubMed  Google Scholar 

  44. Jiang X, West AA, Caudill MA. Maternal choline supplementation: a nutritional approach for improving offspring health? Trends Endocrinol Metab. 2014;25:263–73.

    CAS  PubMed  Google Scholar 

  45. Niculescu MD, Zeisel SHDiet. methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr. 2002;132:2333S–35S.

    CAS  PubMed  Google Scholar 

  46. Meck WH, Williams CL. Metabolic imprinting of choline by its availability during gestation: implications for memory and attentional processing across the lifespan. Neurosci Biobehav Rev. 2003;27:385–99.

    CAS  PubMed  Google Scholar 

  47. Meck WH, Williams CL, Cermak JM, Blusztajn JK. Developmental periods of choline sensitivity provide an ontogenetic mechanism for regulating memory capacity and age-related dementia. Front Integr Neurosci. 2007;1:7.

    PubMed  Google Scholar 

  48. Caudill MA, Strupp BJ, Muscalu L, Nevins JEH, Canfield RL. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double-blind, controlled feeding study. FASEB J. 2018;32:2172–80.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants to S.O. from the National Institute of Aging (2R01AG037637-07) and R.V. from the National Science Foundation (1606833).

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Authors and Affiliations

  1. Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute, Arizona State University, Tempe, AZ, USA

    Ramon Velazquez, Eric Ferreira, Wendy Winslow, Nikhil Dave, An Tran, Antonella Caccamo & Salvatore Oddo

  2. Translational Genomics Research Institute, Phoenix, AZ, USA

    Ignazio S. Piras, Marcus Naymik & Matthew J. Huentelman

  3. School of Life Sciences, Arizona State University, Tempe, AZ, USA

    Salvatore Oddo

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Velazquez, R., Ferreira, E., Winslow, W. et al. Maternal choline supplementation ameliorates Alzheimer’s disease pathology by reducing brain homocysteine levels across multiple generations. Mol Psychiatry 25, 2620–2629 (2020). https://doi.org/10.1038/s41380-018-0322-z

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