Maternal fish-oil supplementation reduces presenilin 1 level and the amyloid-beta burden in adult 5xFAD offspring without major changes in brain fatty acids

Authors

  • Desanka J. Milanović 1Department of Neurobiology, University of Belgrade, Institute for Biological Research “Siniša Stanković” - National Institute of the Republic of Serbia, University of Belgrade, Blvd. Despot Stefan 142, 11108, Belgrade, Serbia https://orcid.org/0000-0001-9799-0335
  • Milka M. Perović 1Department of Neurobiology, University of Belgrade, Institute for Biological Research “Siniša Stanković” - National Institute of the Republic of Serbia, University of Belgrade, Blvd. Despot Stefan 142, 11108, Belgrade, Serbia https://orcid.org/0000-0003-0941-6988
  • Snježana B. Petrović Group for Nutritional Biochemistry and Dietology, Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia https://orcid.org/0000-0002-1387-9777
  • Smilja T. Todorović 1Department of Neurobiology, University of Belgrade, Institute for Biological Research “Siniša Stanković” - National Institute of the Republic of Serbia, University of Belgrade, Blvd. Despot Stefan 142, 11108, Belgrade, Serbia https://orcid.org/0000-0001-7155-4914
  • Milica R. Prvulović 1Department of Neurobiology, University of Belgrade, Institute for Biological Research “Siniša Stanković” - National Institute of the Republic of Serbia, University of Belgrade, Blvd. Despot Stefan 142, 11108, Belgrade, Serbia https://orcid.org/0000-0003-2769-5212
  • Anđela P. Vukojević 1Department of Neurobiology, University of Belgrade, Institute for Biological Research “Siniša Stanković” - National Institute of the Republic of Serbia, University of Belgrade, Blvd. Despot Stefan 142, 11108, Belgrade, Serbia https://orcid.org/0000-0003-2465-903X
  • Aleksandra N. Mladenović 1Department of Neurobiology, University of Belgrade, Institute for Biological Research “Siniša Stanković” - National Institute of the Republic of Serbia, University of Belgrade, Blvd. Despot Stefan 142, 11108, Belgrade, Serbia https://orcid.org/0000-0001-9011-5634

Keywords:

Fish oil, maternal treatment, brain fatty acids, omega-3, Alzheimer's disease

Abstract

Paper description:

  • Early diagnosis and treatment of Alzheimer’s disease (AD) are critical for delaying its progression.
  • The 5×FAD (familial AD) mice model develops amyloid pathology very early limiting the window for nutritional intervention.
  • Maternal supplementation with omega-3-reach fish oil until weaning reduces amyloid burden in adult offspring.
  • Early and sufficient omega-3 dietary intervention can enhance brain resilience to AD-related pathology.

Abstract: Omega-3 fatty acid interventions show potential benefits in Alzheimer’s disease (AD) when initiated during its early stages. This study investigated whether maternal diet supplemented with omega-3-rich fish oil (FO) could delay or reduce amyloid beta (Aβ) formation, a key feature of AD, in 5xFAD transgenic offspring. Dams received FO during mating, pregnancy, and lactation. Brain tissues from female offspring were collected at 2 and 6 months of age. The findings indicated a shift in amyloid precursor protein processing, evidenced by increased soluble amyloid precursor protein α (sAPPα) levels, suggesting a transition from amyloidogenic to non-amyloidogenic pathway. FO influenced the expression of presenilin 1 and 2 but did not impact Aβ levels in 2-month-old mice. However, FO reduced the Aβ burden in the brains of 6-month-old animals. Lipidomic analysis revealed that 5xFAD mice have unimpaired omega-3 acquisition during gestation and lactation in comparison to non-transgenic littermates. However, a response to FO supplementation was found in non-transgenic offspring, indicating that alterations in brain lipids are not the primary mechanism of FO-induced Ab decline in 5xFAD. In conclusion, FO did not prevent or delay amyloid pathology in genetically predisposed animals but did mitigate its progression, suggesting mechanisms that warrant further investigation.

Downloads

Download data is not yet available.

References

Mora I, Arola L, Caimari A, Escote X, Puiggros F. Structured Long-Chain Omega-3 Fatty Acids for Improvement of Cognitive Function during Aging. Int J Mol Sci. 2022;23(7):3472. https://doi.org/10.3390/ijms23073472

Thomas J, Thomas CJ, Radcliffe J, Itsiopoulos C. Omega-3 Fatty Acids in Early Prevention of Inflammatory Neurodegenerative Disease: A Focus on Alzheimer’s Disease. Biomed Res Int. 2015;2015:172801. https://doi.org/10.1155/2015/172801

Sehar U, Rawat P, Reddy AP, Kopel J, Reddy PH. Amyloid Beta in Aging and Alzheimer’s Disease. Int J Mol Sci. 2022;23(21). https://doi.org/10.3390/ijms232112924

Wu T, Lin D, Cheng Y, Jiang S, Riaz MW, Fu N, Mou C, Ye M, Zheng Y. Amyloid Cascade Hypothesis for the Treatment of Alzheimer’s Disease: Progress and Challenges. Aging Dis. 2022;13(6):1745-58. https://doi.org/10.14336/AD.2022.0412

Grimm MO, Kuchenbecker J, Grosgen S, Burg VK, Hundsdorfer B, Rothhaar TL, Friess P, de Wilde MC, Broersen LM, Penke B, Peter M, Vigh L, Grimm HS, Hartmann T. Docosahexaenoic acid reduces amyloid beta production via multiple pleiotropic mechanisms. J Biol Chem. 2011;286(16):14028-39. https://doi.org/10.1074/jbc.M110.182329

Li N, Liu K, Qiu Y, Ren Z, Dai R, Deng Y, Qing H. Effect of Presenilin Mutations on APP Cleavage; Insights into the Pathogenesis of FAD. Front Aging Neurosci. 2016;8:51. https://doi.org/10.3389/fnagi.2016.00051.

Troesch B, Eggersdorfer M, Laviano A, Rolland Y, Smith AD, Warnke I, Weimann A, Calder PC. Expert Opinion on Benefits of Long-Chain Omega-3 Fatty Acids (DHA and EPA) in Aging and Clinical Nutrition. Nutrients. 2020;12(9):2555. https://doi.org/10.3390/nu12092555

Madore C, Leyrolle Q, Morel L, Rossitto M, Greenhalgh AD, Delpech JC, Martinat M, Bosch-Bouju C, Bourel J, Rani B, Lacabanne C, Thomazeau A, Hopperton KE, Beccari S, Sere A, Aubert A, De Smedt-Peyrusse V, Lecours C, Bisht K, Fourgeaud L, Gregoire S, Bretillon L, Acar N, Grant NJ, Badaut J, Gressens P, Sierra A, Butovsky O, Tremblay ME, Bazinet RP, Joffre C, Nadjar A, Laye S. Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain. Nat Commun. 2020;11(1):6133. https://doi.org/10.1038/s41467-020-19861-z

Basak S, Mallick R, Duttaroy AK. Maternal Docosahexaenoic Acid Status during Pregnancy and Its Impact on Infant Neurodevelopment. Nutrients. 2020;12(12):3615. https://doi.org/10.3390/nu12123615

Feng Z, Zou X, Jia H, Li X, Zhu Z, Liu X, Bucheli P, Ballevre O, Hou Y, Zhang W, Wang J, Chen Y, Liu J. Maternal docosahexaenoic acid feeding protects against impairment of learning and memory and oxidative stress in prenatally stressed rats: possible role of neuronal mitochondria metabolism. Antioxid Redox Signal. 2012;16(3):275-89. https://doi.org/10.1089/ars.2010.3750

Teng E, Taylor K, Bilousova T, Weiland D, Pham T, Zuo X, Yang F, Chen PP, Glabe CG, Takacs A, Hoffman DR, Frautschy SA, Cole GM. Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Abeta pathology and modulates Abeta oligomerization. Neurobiol Dis. 2015;82:552-60. https://doi.org/10.1016/j.nbd.2015.09.002

Green KN, Martinez-Coria H, Khashwji H, Hall EB, Yurko-Mauro KA, Ellis L, LaFerla FM. Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels. J Neurosci. 2007;27(16):4385-95. https://doi.org/10.1523/JNEUROSCI.0055-07.2007

Hooijmans CR, Pasker-de Jong PC, de Vries RB, Ritskes-Hoitinga M. The effects of long-term omega-3 fatty acid supplementation on cognition and Alzheimer’s pathology in animal models of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2012;28(1):191-209. https://doi.org/10.3233/JAD-2011-111217

Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N, Jr., Frautschy SA, Cole GM. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005;25(12):3032-40. https://doi.org/10.1523/JNEUROSCI.4225-04.2005

Perez SE, Berg BM, Moore KA, He B, Counts SE, Fritz JJ, Hu YS, Lazarov O, Lah JJ, Mufson EJ. DHA diet reduces AD pathology in young APPswe/PS1 Delta E9 transgenic mice: possible gender effects. J Neurosci Res. 2010;88(5):1026-40. https://doi.org/10.1002/jnr.22266

Park YH, Shin SJ, Kim HS, Hong SB, Kim S, Nam Y, Kim JJ, Lim K, Kim JS, Kim JI, Jeon SG, Moon M. Omega-3 Fatty Acid-Type Docosahexaenoic Acid Protects against Abeta-Mediated Mitochondrial Deficits and Pathomechanisms in Alzheimer's Disease-Related Animal Model. Int J Mol Sci. 2020;21(11). https://doi.org/10.3390/ijms21113879

Jovic M, Loncarevic-Vasiljkovic N, Ivkovic S, Dinic J, Milanovic D, Zlokovic B, Kanazir S. Short-term fish oil supplementation applied in presymptomatic stage of Alzheimer’s disease enhances microglial/macrophage barrier and prevents neuritic dystrophy in parietal cortex of 5xFAD mouse model. PLoS One. 2019;14(5):e0216726. https://doi.org/10.1371/journal.pone.0216726

Milanovic D, Petrovic S, Brkic M, Avramovic V, Perovic M, Ivkovic S, Glibetic M, Kanazir S. Short-Term Fish Oil Treatment Changes the Composition of Phospholipids While Not Affecting the Expression of Mfsd2a Omega-3 Transporter in the Brain and Liver of the 5xFAD Mouse Model of Alzheimer’s Disease. Nutrients. 2018;10(9). https://doi.org/10.3390/nu10091250

Casali BT, Corona AW, Mariani MM, Karlo JC, Ghosal K, Landreth GE. Omega-3 Fatty Acids Augment the Actions of Nuclear Receptor Agonists in a Mouse Model of Alzheimer’s Disease. J Neurosci. 2015;35(24):9173-81. https://doi.org/10.1523/JNEUROSCI.1000-15.2015

Arsenault D, Julien C, Tremblay C, Calon F. DHA improves cognition and prevents dysfunction of entorhinal cortex neurons in 3xTg-AD mice. PLoS One. 2011;6(2):e17397. https://doi.org/10.1371/journal.pone.0017397

Satizabal CL, Himali JJ, Beiser AS, Ramachandran V, Melo van Lent D, Himali D, Aparicio HJ, Maillard P, DeCarli CS, Harris WS, Seshadri S. Association of Red Blood Cell Omega-3 Fatty Acids With MRI Markers and Cognitive Function in Midlife: The Framingham Heart Study. Neurology. 2022;99(23):e2572-82. https://doi.org/10.1212/WNL.0000000000201296

Bazinet RP, Laye S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci. 2014;15(12):771-85. https://doi.org/10.1038/nrn3820

Heath RJ, Wood TR. Why Have the Benefits of DHA Not Been Borne Out in the Treatment and Prevention of Alzheimer’s Disease? A Narrative Review Focused on DHA Metabolism and Adipose Tissue. Int J Mol Sci. 2021;22(21):11826. https://doi.org/10.3390/ijms222111826

Kousparou C, Fyrilla M, Stephanou A, Patrikios I. DHA/EPA (Omega-3) and LA/GLA (Omega-6) as Bioactive Molecules in Neurodegenerative Diseases. Int J Mol Sci. 2023;24(13):10717. https://doi.org/10.3390/ijms241310717

Olivier Kerdiles SL, Frédéric Calon. Omega-3 polyunsaturated fatty acids and brain health: Preclinical evidence for the prevention of neurodegenerative diseases. Trends Food Sci Technol. 2017;69:203-13. https://doi.org/10.1016/j.tifs.2017.09.003

Zhang XW, Chen JY, Ouyang D, Lu JH. Quercetin in Animal Models of Alzheimer’s Disease: A Systematic Review of Preclinical Studies. Int J Mol Sci. 2020;21(2):493. https://doi.org/10.3390/ijms21020493

Meldrum SJ, D'Vaz N, Casadio Y, Dunstan JA, Niels Krogsgaard-Larsen N, Simmer K, Prescott SL. Determinants of DHA levels in early infancy: differential effects of breast milk and direct fish oil supplementation. Prostaglandins Leukot Essent Fatty Acids. 2012;86(6):233-9. https://doi.org/10.1016/j.plefa.2012.03.006

Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006;26(40):10129-40. https://doi.org/10.1523/JNEUROSCI.1202-06.2006

Caselli RJ, Beach TG, Knopman DS, Graff-Radford NR. Alzheimer Disease: Scientific Breakthroughs and Translational Challenges. Mayo Clin Proc. 2017;92(6):978-94. https://doi.org/10.1016/j.mayocp.2017.02.011

Wong MW, Braidy N, Poljak A, Pickford R, Thambisetty M, Sachdev PS. Dysregulation of lipids in Alzheimer’s disease and their role as potential biomarkers. Alzheimers Dement. 2017;13(7):810-27. https://doi.org/10.1016/j.jalz.2017.01.008

Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, Wenk MR, Goh EL, Silver DL. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature. 2014;509(7501):503-6. https://doi.org/10.1038/nature13241

Forner S, Kawauchi S, Balderrama-Gutierrez G, Kramar EA, Matheos DP, Phan J, Javonillo DI, Tran KM, Hingco E, da Cunha C, Rezaie N, Alcantara JA, Baglietto-Vargas D, Jansen C, Neumann J, Wood MA, MacGregor GR, Mortazavi A, Tenner AJ, LaFerla FM, Green KN. Systematic phenotyping and characterization of the 5xFAD mouse model of Alzheimer’s disease. Sci Data. 2021;8(1):270. https://doi.org/10.1038/s41597-021-01054-y

Zirpoli H, Chang CL, Carpentier YA, Michael-Titus AT, Ten VS, Deckelbaum RJ. Novel Approaches for Omega-3 Fatty Acid Therapeutics: Chronic Versus Acute Administration to Protect Heart, Brain, and Spinal Cord. Annu Rev Nutr. 2020;40:161-87. https://doi.org/10.1146/annurev-nutr-082018-124539

Lee JH, Ahn NH, Choi SB, Kwon Y, Yang SH. Natural Products Targeting Amyloid Beta in Alzheimer’s Disease. Int J Mol Sci. 2021;22(5):2341. https://doi.org/10.3390/ijms22052341

Grimm MO, Grimm HS, Hartmann T. Amyloid beta as a regulator of lipid homeostasis. Trends Mol Med. 2007;13(8):337-44. https://doi.org/10.1016/j.molmed.2007.06.004

Deaton CA, Johnson GVW. Presenilin 1 regulates membrane homeostatic pathways that are dysregulated in Alzheimer’s disease. J Alzheimers Dis. 2020;77(3):961-77. https://doi.org/10.3233/JAD-200598

Pizzo P, Basso E, Filadi R, Greotti E, Leparulo A, Pendin D, Redolfi N, Rossini M, Vajente N, Pozzan T, Fasolato C. Presenilin-2 and Calcium Handling: Molecules, Organelles, Cells and Brain Networks. Cells. 2020;9(10):2166. https://doi.org/10.3390/cells9102166

Han J, Park H, Maharana C, Gwon AR, Park J, Baek SH, Bae HG, Cho Y, Kim HK, Sul JH, Lee J, Kim E, Kim J, Cho Y, Park S, Palomera LF, Arumugam TV, Mattson MP, Jo DG. Alzheimer’s disease-causing presenilin-1 mutations have deleterious effects on mitochondrial function. Theranostics. 2021;11(18):8855-73. https://doi.org/10.7150/thno.59776

Sugasini D, Park JC, McAnany JJ, Kim TH, Ma G, Yao X, Antharavally B, Oroskar A, Oroskar AA, Layden BT, Subbaiah PV. Improvement of retinal function in Alzheimer disease-associated retinopathy by dietary lysophosphatidylcholine-EPA/DHA. Sci Rep. 2023;13(1):9179. https://doi.org/10.1038/s41598-023-36268-0

Ordonez-Gutierrez L, Fabrias G, Casas J, Wandosell F. Diets with Higher omega-6/omega-3 Ratios Show Differences in Ceramides and Fatty Acid Levels Accompanied by Increased Amyloid-Beta in the Brains of Male APP/PS1 Transgenic Mice. Int J Mol Sci. 2021;22(20):10907. https://doi.org/10.3390/ijms222010907

Bros-Konopielko M, Bialek A, Johne M, Czajkowski K. Increased LC PUFA Levels in the Serum of Pregnant Women and Their Children as a Result of Dietary Supplementation with ‘Omega’ Fatty Acids. Nutrients. 2023;15(1):231. https://doi.org/10.3390/nu15010231

Grimm MO, Haupenthal VJ, Mett J, Stahlmann CP, Blumel T, Mylonas NT, Endres K, Grimm HS, Hartmann T. Oxidized Docosahexaenoic Acid Species and Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing. Neurodegener Dis. 2016;16(1-2):44-54. https://doi.org/10.1159/000440839

Lee YJ, Jung HW, Kim HY, Choi YJ, Lee YA. Early-Life Exposure to Per- and Poly-Fluorinated Alkyl Substances and Growth, Adiposity, and Puberty in Children: A Systematic Review. Front Endocrinol (Lausanne). 2021;12:683297. https://doi.org/10.3389/fendo.2021.683297

Kim KH, Moon M, Yu SB, Mook-Jung I, Kim JI. RNA-Seq analysis of frontal cortex and cerebellum from 5XFAD mice at early stage of disease pathology. J Alzheimers Dis. 2012;29(4):793-808. https://doi.org/10.3233/JAD-2012-111793

Coniglio S, Shumskaya M, Vassiliou E. Unsaturated Fatty Acids and Their Immunomodulatory Properties. Biology (Basel). 2023;12(2):279. https://doi.org/10.3390/biology12020279

Grimm MOW, Michaelson DM, Hartmann T. Omega-3 fatty acids, lipids, and apoE lipidation in Alzheimer’s disease: a rationale for multi-nutrient dementia prevention. J Lipid Res. 2017;58(11):2083-101. https://doi.org/10.1194/jlr.R076331

Iwao T, Takata F, Matsumoto J, Aridome H, Yasunaga M, Yokoya M, Kataoka Y, Dohgu S. Aging decreases docosahexaenoic acid transport across the blood-brain barrier in C57BL/6J mice. PLoS One. 2023;18(2):e0281946. https://doi.org/10.1371/journal.pone.0281946

Sanchez-Campillo M, Ruiz-Pastor MJ, Gazquez A, Marin-Munoz J, Noguera-Perea F, Ruiz-Alcaraz AJ, Manzanares-Sanchez S, Antunez C, Larque E. Decreased Blood Level of MFSD2a as a Potential Biomarker of Alzheimer's Disease. Int J Mol Sci. 2019;21(1):70. https://doi.org/10.3390/ijms21010070

Wang X, Lin H, Gu Y. Multiple roles of dihomo-gamma-linolenic acid against proliferation diseases. Lipids Health Dis. 2012;11:25. https://doi.org/10.1186/1476-511X-11-25

Nilsen DWT, Myhre PL, Kalstad A, Schmidt EB, Arnesen H, Seljeflot I. Serum Levels of Dihomo-Gamma (gamma)-Linolenic Acid (DGLA) Are Inversely Associated with Linoleic Acid and Total Death in Elderly Patients with a Recent Myocardial Infarction. Nutrients. 2021;13(10):3475. https://doi.org/10.3390/nu13103475

Sergeant S, Rahbar E, Chilton FH. Gamma-linolenic acid, Dihommo-gamma linolenic, Eicosanoids and Inflammatory Processes. Eur J Pharmacol. 2016;785:77-86. https://doi.org/10.1016/j.ejphar.2016.04.020

Mychaleckyj JC, Zhang D, Nayak U, Ross Colgate E, Carmolli M, Dickson D, Ahmed T, Alam M, Kirkpatrick BD, Haque R, Petri WA, Jr. Association of breast milk gamma-linolenic acid with infant anthropometric outcomes in urban, low-income Bangladeshi families: a prospective, birth cohort study. Eur J Clin Nutr. 2020;74(5):698-707. https://doi.org/10.1038/s41430-019-0498-6

Semba RD. Perspective: The potential role of circulating lysophosphatidylcholine in neuroprotection against Alzheimer disease. Adv Nutr. 2020;11(4):760-72. https://doi.org/10.1093/advances/nmaa024

Floris LM, Stahl B, Abrahamse-Berkeveld M, Teller IC. Human milk fatty acid profile across lactational stages after term and preterm delivery: A pooled data analysis. Prostaglandins Leukot Essent Fatty Acids. 2020;156:102023. https://doi.org/10.1016/j.plefa.2019.102023

Downloads

Published

2024-04-24

How to Cite

1.
Milanović DJ, Perović MM, Petrović SB, Todorović ST, Prvulović MR, Vukojević AP, Mladenović AN. Maternal fish-oil supplementation reduces presenilin 1 level and the amyloid-beta burden in adult 5xFAD offspring without major changes in brain fatty acids. Arch Biol Sci [Internet]. 2024Apr.24 [cited 2024Dec.22];76(1):41-53. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/9386

Issue

Vol. 76 No. 1 (2024)

Section

Articles

License

Copyright (c) 2024 Desanka Milanović, Milka Perović, Snjezana Petrović, Smilja Todorović, Milica Prvulović, Anđela Vukojević, Aleksandra Mladenović

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution 4.0 International License that allows others to share the work with an acknowledgment of the work’s authorship and initial publication in this journal.