Skip to main content

Advertisement

SpringerLink
Log in

DHA Selectively Protects SAMP-8-Associated Cognitive Deficits Through Inhibition of JNK

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

A potential role of marine n-3 polyunsaturated fatty acids (ω-3 PUFAs) has been suggested in memory, learning, and cognitive processes. Therefore, ω-3 PUFAs might be a promising treatment option, albeit controversial, for Alzheimer’s disease (AD). Among the different mechanisms that have been proposed as responsible for the beneficial effects of ω-3 PUFAs, inhibition of JNK stands as a particularly interesting candidate. In the present work, it has been studied whether the administration of two different PUFAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and a DHA-derived specialized pro-resolving lipid mediator (MaR1) is able to reverse cognitive deficits in the senescence-accelerated mouse prone 8 (SAMP8) mouse model of sporadic AD. The novel object recognition test (NORT) test showed that recognition memory was significantly impaired in SAMP8 mice, as shown by a significantly decreased discrimination index that was reversed by MaR1 and DHA. In the retention phase of the Morris water maze (MWM) task, SAMP8 mice showed memory deficit that only DHA treatment was able to reverse. pJNK levels were significantly increased in the hippocampus of SAMP8 mice compared to SAMR1 mice, and only DHA treatment was able to significantly reverse these increased pJNK levels. Similar results were found when measuring c-Jun, the main JNK substrate. Consequently to the increases in tau phosphorylation after increased pJNK, it was checked that tau phosphorylation (PHF-1) was increased in SAMP mice, and this effect was reversed after DHA treatment. Altogether, DHA could represent a new approach for the treatment of AD through JNK inhibition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Querfurth HW, Laferla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344. https://doi.org/10.1056/NEJMra0909142

    Article  CAS  PubMed  Google Scholar 

  2. Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM (2016) Alzheimer’s disease. Lancet 388:505–517. https://doi.org/10.1016/S0140-6736(15)01124-1

    Article  CAS  PubMed  Google Scholar 

  3. Abete I, Goyenechea E, Zulet MA, Martínez JA (2011) Obesity and metabolic syndrome: Potential benefit from specific nutritional components. Nutr Metab Cardiovasc Dis 21:B1–B15. https://doi.org/10.1016/j.numecd.2011.05.001

    Article  CAS  PubMed  Google Scholar 

  4. Lorente-Cebrián S, Costa AGV, Navas-Carretero S, Zabala M, Martínez JA, Moreno-Aliaga MJ (2013) Role of omega-3 fatty acids in obesity, metabolic syndrome, and cardiovascular diseases: a review of the evidence. J Physiol Biochem 69:633–651. https://doi.org/10.1007/s13105-013-0265-4

    Article  CAS  PubMed  Google Scholar 

  5. Calder PC (2015) Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance. Biochim Biophys Acta 1851:469–484. https://doi.org/10.1016/j.bbalip.2014.08.010

    Article  CAS  PubMed  Google Scholar 

  6. Kawakita E, Hashimoto M, Shido O (2006) Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neuroscience 139:991–997. https://doi.org/10.1016/j.neuroscience.2006.01.021

    Article  CAS  PubMed  Google Scholar 

  7. He C, Qu X, Cui L, Wang J, Kang JX (2009) Improved spatial learning performance of fat-1 mice is associated with enhanced neurogenesis and neuritogenesis by docosahexaenoic acid. Proc Natl Acad Sci U S A 106:11370–11375. https://doi.org/10.1073/pnas.0904835106

    Article  PubMed  PubMed Central  Google Scholar 

  8. Dagai L, Peri-Naor R, Birk RZ (2009) Docosahexaenoic acid significantly stimulates immediate early response genes and neurite outgrowth. Neurochem Res 34:867–875. https://doi.org/10.1007/s11064-008-9845-z

    Article  CAS  PubMed  Google Scholar 

  9. Belkouch M, Hachem M, Elgot A, Lo Van A, Picq M, Guichardant M, Lagarde M, Bernoud-Hubac N (2016) The pleiotropic effects of omega-3 docosahexaenoic acid on the hallmarks of Alzheimer’s disease. J Nutr Biochem 38:1–11. https://doi.org/10.1016/j.jnutbio.2016.03.002

    Article  CAS  PubMed  Google Scholar 

  10. Burckhardt M, Herke M, Wustmann T, Watzke S, Langer G, Fink A (2016) Omega-3 fatty acids for the treatment of dementia. Cochrane Database Syst Rev 4:CD009002. https://doi.org/10.1002/14651858.CD009002.pub3

    Article  PubMed  Google Scholar 

  11. Conquer JA, Tierney MC, Zecevic J, Bettger WJ, Fisher RH (2000) Fatty acid analysis of blood plasma of patients with Alzheimer’s disease, other types of dementia, and cognitive impairment. Lipids 35:1305–1312

    Article  CAS  PubMed  Google Scholar 

  12. Cunnane SC, Schneider JA, Tangney C, Tremblay-Mercier J, Fortier M, Bennett DA, Morris MC (2012) Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 29:691–697. https://doi.org/10.3233/JAD-2012-110629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lopez LB, Kritz-Silverstein D, Barrett Connor E (2011) High dietary and plasma levels of the omega-3 fatty acid docosahexaenoic acid are associated with decreased dementia risk: the Rancho Bernardo study. J Nutr Health Aging 15:25–31

    Article  CAS  PubMed  Google Scholar 

  14. Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, Tucker KL, Kyle DJ et al (2006) Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol 63:1545–1550. https://doi.org/10.1001/archneur.63.11.1545

    Article  PubMed  Google Scholar 

  15. Laiglesia LM, Lorente-Cebrián S, López-Yoldi M, Lanas R, Sáinz N, Martínez JA, Moreno-Aliaga MJ (2018) Maresin 1 inhibits TNF-alpha-induced lipolysis and autophagy in 3T3-L1 adipocytes. J Cell Physiol 233:2238–2246. https://doi.org/10.1002/jcp.26096

    Article  CAS  PubMed  Google Scholar 

  16. Zhu M, Wang X, Hjorth E, Colas RA, Schroeder L, Granholm AC, Serhan CN, Schultzberg M (2016) Pro-resolving lipid mediators improve neuronal survival and increase Aβ42 phagocytosis. Mol Neurobiol 53:2733–2749. https://doi.org/10.1007/s12035-015-9544-0

    Article  CAS  PubMed  Google Scholar 

  17. Pallas M, Camins A, Smith MA, Perry G, Lee H, Casadesus G (2008) From aging to Alzheimer’s disease: unveiling “the switch” with the senescence-accelerated mouse model (SAMP8). J Alzheimers Dis 15:615–624. https://doi.org/10.3233/JAD-2008-15408

    Article  CAS  PubMed  Google Scholar 

  18. Orejana L, Barros-Miñones L, Aguirre N, Puerta E (2013) Implication of JNK pathway on tau pathology and cognitive decline in a senescence-accelerated mouse model. Exp Gerontol 48:565–571. https://doi.org/10.1016/j.exger.2013.03.001

    Article  CAS  PubMed  Google Scholar 

  19. Dobarro M, Orejana L, Aguirre N, Ramírez MJ (2013) Propranolol restores cognitive deficits and improves amyloid and tau pathologies in a senescence-accelerated mouse model. Neuropharmacology 64:137–144. https://doi.org/10.1016/j.neuropharm.2012.06.047

    Article  CAS  PubMed  Google Scholar 

  20. Cui J, Zhang M, Zhang YQ, Xu ZH (2007) JNK pathway: diseases and therapeutic potential. Acta Pharmacol Sin 28:601–608. https://doi.org/10.1111/j.1745-7254.2007.00579.x

    Article  CAS  PubMed  Google Scholar 

  21. Antoniou X, Falconi M, Di Marino D, Borsello T (2011) JNK3 as a therapeutic target for neurodegenerative diseases. J Alzheimers Dis 24:633–642. https://doi.org/10.3233/JAD-2011-091567

    Article  CAS  PubMed  Google Scholar 

  22. Pearson AG, Byrne UTE, MacGibbon GA, Faull RLM, Dragunow M (2006) Activated c-Jun is present in neurofibrillary tangles in Alzheimer’s disease brains. Neurosci Lett 398:246–250. https://doi.org/10.1016/j.neulet.2006.01.031

    Article  CAS  PubMed  Google Scholar 

  23. Kolarova M, García-Sierra F, Bartos A, Ricny J, Ripova D (2012) Structure and pathology of tau protein in Alzheimer disease. Int J Alzheimers Dis 2012:731526. https://doi.org/10.1155/2012/731526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Marques CA, Keil U, Bonert A, Steiner B, Haass C, Muller WE, Eckert A (2003) Neurotoxic mechanisms caused by the Alzheimer’s disease-linked Swedish amyloid precursor protein mutation: oxidative stress, caspases, and the JNK pathway. J Biol Chem 278:28294–28302. https://doi.org/10.1074/jbc.M212265200

    Article  CAS  PubMed  Google Scholar 

  25. Sahara N, Murayama M, Lee B, Park JMM, Lagalwar S, Binder LI, Takashima A (2008) Active c-jun N-terminal kinase induces caspase cleavage of tau and additional phosphorylation by GSK-3beta is required for tau aggregation. Eur J Neurosci 27:2897–2906. https://doi.org/10.1111/j.1460-9568.2008.06258.x

    Article  PubMed  Google Scholar 

  26. Yarza R, Vela S, Solas M, Ramirez MJ (2016) c-Jun N-terminal kinase (JNK) signaling as a therapeutic target for Alzheimer’s disease. Front Pharmacol 6:1–12. https://doi.org/10.3389/fphar.2015.00321

    Article  CAS  Google Scholar 

  27. Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, Hudspeth B et al (2009) Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by Omega-3 fatty acids and curcumin. J Neurosci 29:9078–9089. https://doi.org/10.1523/JNEUROSCI.1071-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Casali BT, Corona AW, Mariani MM, Karlo JC, Ghosal K, Landreth GE (2015) Omega-3 fatty acids augment the actions of nuclear receptor agonists in a mouse model of Alzheimer’s disease. J Neurosci 35:9173–9181. https://doi.org/10.1523/JNEUROSCI.1000-15.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Teng E, Taylor K, Bilousova T, Weiland D, Pham T, Zuo X, Yang F, Chen PP et al (2015) Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aβ pathology and modulates Aβ oligomerization. Neurobiol Dis 82:552–560. https://doi.org/10.1016/j.nbd.2015.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, Galvin JE, Emond J et al (2010) Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA 304:1903–1911. https://doi.org/10.1001/jama.2010.1510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B et al (2006) Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol 63:1402–1408. https://doi.org/10.1001/archneur.63.10.1402

    Article  PubMed  Google Scholar 

  32. van de Rest O, Geleijnse JM, Kok FJ, van Staveren WA, Dullemeijer C, Olderikkert MG, Beekman AT, de Groot CP (2008) Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology 71:430–438. https://doi.org/10.1212/01.wnl.0000324268.45138.86

    Article  CAS  PubMed  Google Scholar 

  33. Dangour AD, Allen E, Elbourne D, Fasey N, Fletcher AE, Hardy P, Holder GE, Knight R et al (2010) Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Am J Clin Nutr 91:1725–1732. https://doi.org/10.3945/ajcn.2009.29121

    Article  CAS  PubMed  Google Scholar 

  34. Hosokawa M, Kasai R, Higuchi K, Takeshita S, Shimizu K, Hamamoto H, Honma A, Irino M et al (1984) Grading score system: a method for evaluation of the degree of senescence in senescence accelerated mouse (SAM). Mech Ageing Dev 26:91–102. https://doi.org/10.1016/0047-6374(84)90168-4

    Article  CAS  PubMed  Google Scholar 

  35. Takeda T, Hosokawa M, Higuchi K, Hosono M, Akiguchi I, Katoh H (1994) A novel murine model of aging, senescence-accelerated mouse (SAM). Arch Gerontol Geriatr 19:185–192

    Article  CAS  PubMed  Google Scholar 

  36. McAuley JD, Miller JP, Beck E, Nagy ZM, Pang KCH (2002) Age-related disruptions in circadian timing: evidence for “split” activity rhythms in the SAMP8. Neurobiol Aging 23:625–632. https://doi.org/10.1016/S0197-4580(01)00344-X

    Article  PubMed  Google Scholar 

  37. Alvarez-García O, Vega-Naredo I, Sierra V, Caballero B, Tomás-Zapico C, Camins A, García JJ, Pallàs M et al (2006) Elevated oxidative stress in the brain of senescence-accelerated mice at 5 months of age. Biogerontology 7:43–52. https://doi.org/10.1007/s10522-005-6041-2

    Article  CAS  PubMed  Google Scholar 

  38. Bayram B, Ozcelik B, Grimm S, Roeder T, Schrader C, Ernst IM, Wagner AE, Grune T et al (2012) A diet rich in olive oil phenolics reduces oxidative stress in the heart of SAMP8 mice by induction of Nrf2-dependent gene expression. Rejuvenation Res 15:71–81. https://doi.org/10.1089/rej.2011.1245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Petursdottir AL, Farr SA, Morley JE, Banks WA, Skuladottir GV (2007) Lipid peroxidation in brain during aging in the senescence-accelerated mouse (SAM). Neurobiol Aging 28:1170–1178. https://doi.org/10.1016/j.neurobiolaging.2006.05.033

    Article  CAS  PubMed  Google Scholar 

  40. Kawamata T, Akiguchi I, Yagi H, Irino M, Sugiyama H, Akiyama H, Shimada A, Takemura M et al (1997) Neuropathological studies on strains of senescence-accelerated mice (SAM) with age-related deficits in learning and memory. Exp Gerontol 32:161–169. https://doi.org/10.1016/S0531-5565(96)00063-0

    Article  CAS  PubMed  Google Scholar 

  41. Cuesta S, Kireev R, Forman K, García C, Escames G, Ariznavarreta C, Vara E, Tresguerres JA (2010) Melatonin improves inflammation processes in liver of senescence-accelerated prone male mice (SAMP8). Exp Gerontol 45:950–956. https://doi.org/10.1016/j.exger.2010.08.016

    Article  CAS  PubMed  Google Scholar 

  42. Tha KK, Okuma Y, Miyazaki H, Murayama T, Uehara T, Hatakeyama R, Hayashi Y, Nomura Y (2000) Changes in expressions of proinflammatory cytokines IL-1beta, TNF-alpha and IL-6 in the brain of senescence accelerated mouse (SAM) P8. Brain Res 885:25–31. https://doi.org/10.1016/S0006-8993(00)02883-3

    Article  CAS  PubMed  Google Scholar 

  43. Carretero M, Escames G, López LC, Venegas C, Dayoub JC, García L, Acuña-Castroviejo D (2009) Long-term melatonin administration protects brain mitochondria from aging. J Pineal Res 47:192–200. https://doi.org/10.1111/j.1600-079X.2009.00700.x

    Article  CAS  PubMed  Google Scholar 

  44. Gong Y, Liu L, Xie B, Liao Y, Yang E, Sun Z (2008) Ameliorative effects of lotus seedpod proanthocyanidins on cognitive deficits and oxidative damage in senescence-accelerated mice. Behav Brain Res 194:100–107. https://doi.org/10.1016/j.bbr.2008.06.029

    Article  CAS  PubMed  Google Scholar 

  45. Del Valle J, Duran-Vilaregut J, Manich G, Camins A, Pallàs M, Vilaplana J, Pelegrí C (2009) Time-course of blood-brain barrier disruption in senescence-accelerated mouse prone 8 (SAMP8) mice. Int J Dev Neurosci 27:47–52. https://doi.org/10.1016/j.ijdevneu.2008.10.002

    Article  CAS  PubMed  Google Scholar 

  46. Pelegrí C, Canudas AM, del Valle J, Casadesus G, Smith MA, Camins A, Pallàs M, Vilaplana J (2007) Increased permeability of blood–brain barrier on the hippocampus of a murine model of senescence. Mech Ageing Dev 128:522–528. https://doi.org/10.1016/j.mad.2007.07.002

    Article  CAS  PubMed  Google Scholar 

  47. Morley JE, Armbrecht HJ, Farr SA, Kumar VB (2012) The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis 1822:650–656. https://doi.org/10.1016/j.bbadis.2011.11.015

    Article  CAS  Google Scholar 

  48. Pallàs M (2012) Senescence-accelerated mice P8: a tool to study brain aging and Alzheimer’s disease in a mouse model. ISRN Cell Biol 2012:1–12

    Article  Google Scholar 

  49. Tomobe K, Nomura Y (2009) Neurochemistry, neuropathology, and heredity in SAMP8: a mouse model of senescence. Neurochem Res 34:660–669. https://doi.org/10.1007/s11064-009-9923-x

    Article  CAS  PubMed  Google Scholar 

  50. Woodruff-Pak DS (2008) Animal models of Alzheimer’s disease: therapeutic implications. J Alzheimers Dis 15:507–521. https://doi.org/10.3233/JAD-2008-15401

    Article  CAS  PubMed  Google Scholar 

  51. Eckert GP, Lipka U, Muller WE (2013) Omega-3 fatty acids in neurodegenerative diseases: focus on mitochondria. Prostaglandins Leukot Essent Fat Acids 88:105–114. https://doi.org/10.1016/j.plefa.2012.05.006

    Article  CAS  Google Scholar 

  52. de Souza Fernandes DP, Canaan Rezende FA, Pereira Rocha G, De Santis Filgueiras M, Silva Moreira PR, Gonçalves Alfenas Rde C (2015) Effect of eicosapentaenoic acd and docosahexaenoic acid supplementatations to control cognitive decline in dementia and Alzheimer’s disease: a systematic review. Nutr Hosp 32:528–533. https://doi.org/10.3305/nh.2015.32.2.9111

    Article  PubMed  Google Scholar 

  53. Salem N Jr, Vandal M, Calon F (2015) The benefit of docosahexaenoic acid for the adult brain in aging and dementia. Prostaglandins Leukot Essent Fat Acids 92:15–22. https://doi.org/10.1016/j.plefa.2014.10.003

    Article  CAS  Google Scholar 

  54. Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A et al (2004) Docosahexaenoic acid protects from dendritic pathology in an Alzheimer’s disease mouse model. Neuron 43:633–645. https://doi.org/10.1016/j.neuron.2004.08.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA et al (2005) A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci 25:3032–3040. https://doi.org/10.1523/JNEUROSCI.4225-04.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Petursdottir AL, Farr SA, Morley JE, Banks WA, Skuladottir GV (2008) Effect of dietary n-3 polyunsaturated fatty acids on brain lipid fatty acid composition, learning ability, and memory of senescence-accelerated mouse. J Gerontol A Biol Sci Med Sci 63:1153–1160

    Article  PubMed  Google Scholar 

  58. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Wilson RS, Aggarwal N, Schneider J (2003) Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol 60:940–946. https://doi.org/10.1001/archneur.60.7.940

    Article  PubMed  Google Scholar 

  59. Wu FJ, Xue Y, Liu XF, Xue CH, Wang JF, Du L, Takahashi K, Wang YM (2014) The protective effect of eicosapentaenoic acid-enriched phospholipids from sea cucumber Cucumaria frondosa on oxidative stress in PC12 cells and SAMP8 mice. Neurochem Int 64:9–17. https://doi.org/10.1016/j.neuint.2013.10.015

    Article  CAS  PubMed  Google Scholar 

  60. Zhang F, Jiang L (2015) Neuroinflammation in Alzheimer’s disease. Neuropsychiatr Dis Treat 11:243–256. https://doi.org/10.2147/NDT.S75546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shah SZA, Zhao D, Hussain T, Yang L (2017) The role of unfolded protein response and mitogen-activated protein kinase signaling in neurodegenerative diseases with special focus on prion diseases. Front Aging Neurosci 9:120. https://doi.org/10.3389/fnagi.2017.00120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhang SJ, Xu TT, Li L, Xu YM, Qu ZL, Wang XC, Huang SQ, Luo Y et al (2017) Bushen-Yizhi formula ameliorates cognitive dysfunction through SIRT1/ER stress pathway in SAMP8 mice. Oncotarget 8:49338–49350. https://doi.org/10.18632/oncotarget.17638

    Article  PubMed  PubMed Central  Google Scholar 

  63. Torres M, Marcilla-Etxenike A, Fiol-deRoque MA, Escribá PV, Busquets X (2015) The unfolded protein response in the therapeutic effect of hydroxy-DHA against Alzheimer’s disease. Apoptosis 20:712–724. https://doi.org/10.1007/s10495-015-1099-z

    Article  CAS  PubMed  Google Scholar 

  64. Zeke A, Misheva M, Reményi A, Bogoyevitch MA (2016) JNK signaling: regulation and functions based on complex protein-protein partnerships. Microbiol Mol Biol Rev 80:793–835. https://doi.org/10.1128/MMBR.00043-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dérijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ (1994) JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76:1025–1037. https://doi.org/10.1016/0092-8674(94)90380-8

    Article  PubMed  Google Scholar 

  66. Barros-Miñones L, Orejana L, Goñi-Allo B, Suquía V, Hervías I, Aguirre N, Puerta E (2013) Modulation of the ASK1-MKK3/6-p38/MAPK signalling pathway mediates sildenafil protection against chemical hypoxia caused by malonate. Br J Pharmacol 168:1820–1834. https://doi.org/10.1111/bph.12071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Reddy CE, Albanito L, De Marco P, Aiello D, Maggiolini M, Napoli A, Musti AM (2013) Multisite phosphorylation of c-Jun at threonine 91/93/95 triggers the onset of c-Jun pro-apoptotic activity in cerebellar granule neurons. Cell Death Dis 4:e852. https://doi.org/10.1038/cddis.2013.381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ploia C, Antoniou X, Sclip A, Grande V, Cardinetti D, Colombo A, Canu N, Benussi L et al (2011) JNK plays a key role in tau hyperphosphorylation in Alzheimer’s disease models. J Alzheimers Dis 26:315–329. https://doi.org/10.3233/JAD-2011-110320

    Article  CAS  PubMed  Google Scholar 

  69. Morley JE, Farr SA, Kumar VB, Armbrecht HJ (2012) The SAMP8 mouse: a model to develop therapeutic interventions for Alzheimer’s disease. Curr Pharm Des 18:1123–1130

    Article  CAS  PubMed  Google Scholar 

  70. Tatebayashi Y, Planel E, Chui DH, Sato S, Miyasaka T, Sahara N, Murayama M, Kikuchi N et al (2006) c-jun N-terminal kinase hyperphosphorylates R406W tau at the PHF-1 site during mitosis. FASEB J 20:762–764. https://doi.org/10.1096/fj.05-4362fje

    Article  CAS  PubMed  Google Scholar 

  71. Nguyen LN, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X, Wenk MR, Goh EL et al (2014) Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 509:503–506. https://doi.org/10.1038/nature13241

    Article  CAS  PubMed  Google Scholar 

  72. Cole GM, Ma QL, Frautschy SA (2009) Omega-3 fatty acids and dementia. Prostaglandins Leukot Essent Fat Acids 81:213–221. https://doi.org/10.1016/j.plefa.2009.05.015

    Article  CAS  Google Scholar 

  73. Glass KC, Olefsky JM (2012) Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab 15:635–645. https://doi.org/10.1016/j.cmet.2012.04.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was funded by grants from ISCIII–Subdirección General de Evaluación y Fomento de la Investigación (FIS 13/00858) to M.J.R, Department of Health, Navarra Government (67-2015), MINECO/FEDER (BFU2015-65937-R) to M.J.M-A; and CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Carlos III Health Research Institute (CB12/03/30002).

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain

    S. Vela, M. Solas & María J. Ramirez

  2. Centre for Nutrition Research, University of Navarra, Pamplona, Spain

    Neira Sainz & María J. Moreno-Aliaga

  3. Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain

    María J. Moreno-Aliaga

  4. CIBERobn, Physiopathology of Obesity and Nutrition, Institute of Health Carlos III (ISCIII), Madrid, Spain

    María J. Moreno-Aliaga

  5. IdiSNA, Navarra Institute for Health Research, Pamplona, Spain

    María J. Moreno-Aliaga, M. Solas & María J. Ramirez

Authors
  1. S. Vela
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neira Sainz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. María J. Moreno-Aliaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Solas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. María J. Ramirez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to María J. Ramirez.

Ethics declarations

Experimental procedures were conducted in accordance with the European and Spanish regulations (2003/65/EC; 1201/2005) for the care and use of laboratory animals and approved by the Ethical Committee of University of Navarra (068-11)

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vela, S., Sainz, N., Moreno-Aliaga, M.J. et al. DHA Selectively Protects SAMP-8-Associated Cognitive Deficits Through Inhibition of JNK. Mol Neurobiol 56, 1618–1627 (2019). https://doi.org/10.1007/s12035-018-1185-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1185-7

Keywords

Search

Navigation