Gestational high fat diet protects 3xTg offspring from memory impairments, synaptic dysfunction, and brain pathology

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Abstract

Maternal history for sporadic Alzheimer’s disease (AD) predisposes the offspring to the disease later in life. However, the mechanisms behind this phenomenon are still unknown. Lifestyle and nutrition can directly modulate susceptibility to AD. Herein we investigated whether gestational high fat diet influences the offspring susceptibility to AD later in life. Triple transgenic dams were administered high fat diet or regular chow throughout 3 weeks gestation. Offspring were fed regular chow throughout their life and tested for spatial learning and memory, brain amyloidosis, tau pathology, and synaptic function. Gestational high fat diet attenuated memory decline, synaptic dysfunction, amyloid-β and tau neuropathology in the offspring by transcriptional regulation of BACE-1, CDK5, and tau gene expression via the upregulation of FOXP2 repressor. Gestational high fat diet protects offspring against the development of the AD phenotype. In utero dietary intervention could be implemented as preventative strategy against AD.

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References

  1. 1.

    Barker WW, Luis CA, Kashuba A, Luis M, Harwood DG, Loewenstein D, et al. Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord. 2002;16:203–12.

  2. 2.

    Wilson RS, Segawa E, Boyle PA, Anagnos SE, Hizel LP, Bennett DA. The natural history of cognitive decline in Alzheimer’s disease. Psychol Aging. 2012;27:1008–17.

  3. 3.

    Association As. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement. 2016;12:459–509.

  4. 4.

    Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362:329–44.

  5. 5.

    Duara R, Lopez-Alberola RF, Barker WW, Loewenstein DA, Zatinsky M, Eisdorfer CE, et al. A comparison of familial and sporadic Alzheimer’s disease. Neurology. 1993;43:1377–84.

  6. 6.

    Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278:1349–56.

  7. 7.

    Gómez-Tortosa E, Barquero MS, Barón M, Sainz MJ, Manzano S, Payno M, et al. Variability of age at onset in siblings with familial Alzheimer disease. Arch Neurol. 2007;64:1743–8.

  8. 8.

    Heyman A, Wilkinson WE, Hurwitz BJ, Schmechel D, Sigmon AH, Weinberg T, et al. Alzheimer’s disease: genetic aspects and associated clinical disorders. Ann Neurol. 1983;14:507–15.

  9. 9.

    Mosconi L, Berti V, Swerdlow RH, Pupi A, Duara R, de Leon M. Maternal transmission of Alzheimer’s disease: prodromal metabolic phenotype and the search for genes. Hum Genom. 2010;4:170–93.

  10. 10.

    Mosconi L, de Leon M, Murray J, EL, Lu J, Javier E, et al. Reduced mitochondria cytochrome oxidase activity in adult children of mothers with Alzheimer’s disease. J Alzheimers Dis. 2011;27:483–90.

  11. 11.

    Arab L, Sabbagh MN. Are certain lifestyle habits associated with lower Alzheimer’s disease risk? J Alzheimers Dis. 2010;20:785–94.

  12. 12.

    Creegan R, Hunt W, McManus A, Rainey-Smith SR. Diet, nutrients and metabolism: cogs in the wheel driving Alzheimer’s disease pathology? Br J Nutr. 2015;113:1499–517.

  13. 13.

    Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA. 2008;105:17046–9.

  14. 14.

    Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J. Epigenetic mechanisms in Alzheimer’s disease. Neurobiol Aging. 2011;32:1161–80.

  15. 15.

    Lin B, Hasegawa Y, Takane K, Koibuchi N, Cao C, Kim-Mitsuyama S. High-fat-diet intake enhances cerebral amyloid angiopathy and cognitive impairment in a Mouse Model of Alzheimer’s Disease, independently of metabolic disorders. J Am Heart Assoc. 2016;5:e003154.

  16. 16.

    Sah SK, Lee C, Jang JH, Park GH. Effect of high-fat diet on cognitive impairment in triple-transgenic mice model of Alzheimer’s disease. Biochem Biophys Res Commun. 2017;493:731–6.

  17. 17.

    Thériault P, ElAli A, Rivest S. High fat diet exacerbates Alzheimer’s disease-related pathology in APPswe/PS1 mice. Oncotarget. 2016;7:67808–27.

  18. 18.

    Li SW, Yu HR, Sheen JM, Tiao MM, Tain YL, Lin IC, et al. A maternal high-fat diet during pregnancy and lactation, in addition to a postnatal high-fat diet, leads to metabolic syndrome with spatial learning and memory deficits: beneficial effects of resveratrol. Oncotarget. 2017;8:111998–2013.

  19. 19.

    Martin SA, Jameson CH, Allan SM, Lawrence CB. Maternal high-fat diet worsens memory deficits in the triple-transgenic (3xTgAD) mouse model of Alzheimer’s disease. PLoS ONE. 2014;9:e99226.

  20. 20.

    Nizari S, Carare RO, Hawkes CA. Increased Aβ pathology in aged Tg2576 mice born to mothers fed a high fat diet. Sci Rep. 2016;6:21981.

  21. 21.

    Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003;39:409–21.

  22. 22.

    Di Meco A, Joshi YB, Praticò D. Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer’s disease with plaques and tangles. Neurobiol Aging. 2014;35:1813–20.

  23. 23.

    Di Meco A, Lauretti E, Vagnozzi AN, Praticò D. Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer’s disease mice. Neurobiol Aging. 2014;35:2458–64.

  24. 24.

    Giannopoulos PF, Chu J, Joshi YB, Sperow M, Li JG, Kirby LG, et al. 5-lipoxygenase activating protein reduction ameliorates cognitive deficit, synaptic dysfunction, and neuropathology in a mouse model of Alzheimer’s disease. Biol Psychiatry. 2013;74:348–56.

  25. 25.

    Maegawa S, Hinkal G, Kim HS, Shen L, Zhang L, Zhang J, et al. Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res. 2010;20:332–40.

  26. 26.

    Maegawa S, Lu Y, Tahara T, Lee JT, Madzo J, Liang S, et al. Caloric restriction delays age-related methylation drift. Nat Commun. 2017;8:539.

  27. 27.

    Jicha GA, Bowser R, Kazam IG, Davies P. Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res. 1997;48:128–32.

  28. 28.

    Zucker RS, Regehr WG. Short-term synaptic plasticity. Annu Rev Physiol. 2002;64:355–405.

  29. 29.

    Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361:31–39.

  30. 30.

    Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23:5293–5300.

  31. 31.

    Yang AS, Estécio MR, Doshi K, Kondo Y, Tajara EH, Issa JP. A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res. 2004;32:e38.

  32. 32.

    Bernstein HG, Kirches E, Bogerts B, Lendeckel U, Keilhoff G, Zempeltzi M, et al. Wide distribution of CREM immunoreactivity in adult and fetal human brain, with an increased expression in dentate gyrus neurons of Alzheimer’s as compared to normal aging brains. Amino Acids. 2013;45:1373–83.

  33. 33.

    López-González I, Palmeira A, Aso E, Carmona M, Fernandez L, Ferrer I. FOXP2 expression in frontotemporal lobar degeneration-tau. J Alzheimers Dis. 2016;54:471–5.

  34. 34.

    Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, et al. REST and stress resistance in ageing and Alzheimer’s disease. Nature. 2014;507:448–54.

  35. 35.

    Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA. Midlife serum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later. Dement Geriatr Cogn Disord. 2009;28:75–80.

  36. 36.

    Busquets O, Ettcheto M, Pallàs M, Beas-Zarate C, Verdaguer E, Auladell C, et al. Long-term exposition to a high fat diet favors the appearance of β-amyloid depositions in the brain of C57BL/6J mice. A potential model of sporadic Alzheimer’s disease. Mech Ageing Dev. 2017;162:38–45.

  37. 37.

    Kessler AR, Kessler B, Yehuda S. In vivo modulation of brain cholesterol level and learning performance by a novel plant lipid: indications for interactions between hippocampal-cortical cholesterol and learning. Life Sci. 1986;38:1185–92.

  38. 38.

    Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, Sambamurti K, Kindy MS, et al. High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice. J Neurochem. 2008;106:475–85.

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Acknowledgements

Special thanks to Dr Margaret Sperow and Dr Lynn Kirby for technical assistance in the electrophysiology experiments, and to Dr Peter Davies for providing the MC1 antibody. DP is the Scott Richards North Star Charitable Foundation Chair for Alzheimer’s Research. This study was supported in part by grants from the National Institute of Health (AG060711), and the Scott Richards North Star Charitable Foundation.

Author information

ADM and DP designed the study. ADM, EL, and MEC performed the experiments. JJ, J-PJI and ADM designed and performed the methylation studies. ADM and DP wrote the paper. All authors have discussed the results and seen the final version of the paper before submission.

Correspondence to Domenico Praticό.

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