Skip to content
2000
Volume 25, Issue 19
  • ISSN: 1568-0266
  • E-ISSN: 1873-4294

Abstract

Background

Organophosphate pesticides such as diazinon (DZN) are involved in developing psychological symptoms and memory deficits, but their effects on the amyloid precursor proteins (APP) gene expression remain unclear.

Materials and Methods

Following low-level oral exposure to the DZN (2 mg/kg), we used novel object recognition, open field, and elevated plus-mazes (EPM) to assess memory and anxiety-like behaviors in rats. We also evaluated alteration in the levels of tumor necrosis factor (TNF-α), amyloid precursor protein (APP), APP-like protein-2 (APLP2), and amyloid-β (Aβ) western blotting and ELISA. Real-time quantitative PCR was performed to evaluate the expression of the related genes in the hippocampus.

Results

The findings demonstrated that whereas DZN exposure boosted anxiety-like behaviors at any exposure level, only prolonged exposure (12 weeks) resulted in memory impairment. The study also found that the hippocampal expression of APP and APLP2 decreased after 12 weeks of exposure but not after 5 days. Additionally, Aβ increased after long-lasting exposure to DZN, indicating the APP contribution to AD pathologies. The TNF-α gene was up-regulated following 5 days of exposure, but 12 weeks had no effect.

Conclusion

Our finding demonstrates that long-lasting exposure to low levels of DZN in adulthood stimulates APP degradation, possibly contributing to poor cognitive outcomes.

Loading

Article metrics loading...

/content/journals/ctmc/10.2174/0115680266363758250306052044
2025-03-13
2025-12-30
Loading full text...

Full text loading...

References

  1. KarimaniA. RamezaniN. Afkhami GoliA. Nazem ShiraziM.H. NouraniH. JafariA.M. Subchronic neurotoxicity of diazinon in albino mice: Impact of oxidative stress, AChE activity, and gene expression disturbances in the cerebral cortex and hippocampus on mood, spatial learning, and memory function.Toxicol. Rep.202181280128810.1016/j.toxrep.2021.06.017 34277358
    [Google Scholar]
  2. BaltazarM.T. Dinis-OliveiraR.J. de Lourdes BastosM. TsatsakisA.M. DuarteJ.A. CarvalhoF. Pesticides exposure as etiological factors of Parkinson’s disease and other neurodegenerative diseases—A mechanistic approach.Toxicol. Lett.201423028510310.1016/j.toxlet.2014.01.039 24503016
    [Google Scholar]
  3. SarailooM. AfshariS. AsghariazarV. SafarzadehE. DadkhahM. Cognitive impairment and neurodegenerative diseases development associated with organophosphate pesticides exposure: A review study.Neurotox. Res.20224051624164310.1007/s12640‑022‑00552‑0 36066747
    [Google Scholar]
  4. AloizouA.M. SiokasV. VogiatziC. PeristeriE. DoceaA.O. PetrakisD. ProvatasA. FoliaV. ChalkiaC. VincetiM. WilksM. IzotovB.N. TsatsakisA. BogdanosD.P. DardiotisE. Pesticides, cognitive functions and dementia: A review.Toxicol. Lett.2020326315110.1016/j.toxlet.2020.03.005 32145396
    [Google Scholar]
  5. GiambòF. LeoneG.M. GattusoG. RizzoR. CosentinoA. CinàD. TeodoroM. CostaC. TsatsakisA. FengaC. FalzoneL. Genetic and epigenetic alterations induced by pesticide exposure: Integrated analysis of gene expression, microRNA expression, and DNA methylation datasets.Int. J. Environ. Res. Public Health20211816869710.3390/ijerph18168697 34444445
    [Google Scholar]
  6. HawkeyA. PippenE. WhiteH. KimJ. GreengroveE. KenouB. HollowayZ. LevinE.D. Gestational and perinatal exposure to diazinon causes long-lasting neurobehavioral consequences in the rat.Toxicology202042915232710.1016/j.tox.2019.152327 31704166
    [Google Scholar]
  7. AsghariazarV. KadkhodayiM. MansooriB. MohammadiA. BaradaranB. Restoration of miR-143 reduces migration and proliferation of bladder cancer cells by regulating signaling pathways involved in EMT.Mol. Cell. Probes20226110179410.1016/j.mcp.2022.101794 35121085
    [Google Scholar]
  8. PereiraJ.B. JanelidzeS. OssenkoppeleR. KvartsbergH. BrinkmalmA. Mattsson-CarlgrenN. StomrudE. SmithR. ZetterbergH. BlennowK. HanssonO. Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer’s disease.Brain2021144131032410.1093/brain/awaa395 33279949
    [Google Scholar]
  9. Mattsson-CarlgrenN. AnderssonE. JanelidzeS. OssenkoppeleR. InselP. StrandbergO. ZetterbergH. RosenH.J. RabinoviciG. ChaiX. BlennowK. DageJ.L. StomrudE. SmithR. PalmqvistS. HanssonO. Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease.Sci. Adv.2020616eaaz238710.1126/sciadv.aaz2387 32426454
    [Google Scholar]
  10. ZhanL. ZhouJ. WangY. JinY. JahanshadN. PrasadG. NirT.M. LeonardoC.D. YeJ. ThompsonP.M. Comparison of nine tractography algorithms for detecting abnormal structural brain networks in Alzheimer’s disease.Front. Aging Neurosci.201574810.3389/fnagi.2015.00048 25926791
    [Google Scholar]
  11. DeytsC. APP-mediated signaling prevents memory decline in alzheimer’s disease mouse model.Cell Rep.201927513451355
    [Google Scholar]
  12. FolkeJ. PakkenbergB. BrudekT. Impaired Wnt signaling in the prefrontal cortex of Alzheimer’s disease.Mol. Neurobiol.201956287389110.1007/s12035‑018‑1103‑z 29804228
    [Google Scholar]
  13. LiuM. LiF. YanH. WangK. MaY. ShenL. XuM. A multi-model deep convolutional neural network for automatic hippocampus segmentation and classification in Alzheimer’s disease.Neuroimage202020811645910.1016/j.neuroimage.2019.116459 31837471
    [Google Scholar]
  14. Meyer-BaronM. KnappG. SchäperM. van ThrielC. Meta-analysis on occupational exposure to pesticides – Neurobehavioral impact and dose–response relationships.Environ. Res.201513623424510.1016/j.envres.2014.09.030 25460642
    [Google Scholar]
  15. SteenlandK. DickR.B. HowellR.J. ChrislipD.W. HinesC.J. ReidT.M. LehmanE. LaberP. KriegE.F.Jr KnottC. Neurologic function among termiticide applicators exposed to chlorpyrifos.Environ. Health Perspect.2000108429330010.1289/ehp.00108293 10753086
    [Google Scholar]
  16. SavyC.Y. FitchettA.E. BlainP.G. MorrisC.M. JudgeS.J. Gene expression analysis reveals chronic low level exposure to the pesticide diazinon affects psychological disorders gene sets in the adult rat.Toxicology20183939010110.1016/j.tox.2017.11.006 29108742
    [Google Scholar]
  17. AydinD. WeyerS.W. MüllerU.C. Functions of the APP gene family in the nervous system: Insights from mouse models.Exp. Brain Res.20122173-442343410.1007/s00221‑011‑2861‑2 21931985
    [Google Scholar]
  18. WalkerJ.M. FowlerS.W. MillerD.K. SunA.Y. WeismanG.A. WoodW.G. SunG.Y. SimonyiA. SchachtmanT.R. Spatial learning and memory impairment and increased locomotion in a transgenic amyloid precursor protein mouse model of Alzheimer’s disease.Behav. Brain Res.2011222116917510.1016/j.bbr.2011.03.049 21443906
    [Google Scholar]
  19. WeyerS.W. ZagrebelskyM. HerrmannU. HickM. GanssL. GobbertJ. GruberM. AltmannC. KorteM. DellerT. MüllerU.C. Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsα expression.Acta Neuropathol. Commun.2014213610.1186/2051‑5960‑2‑36 24684730
    [Google Scholar]
  20. HardyJ. SelkoeD.J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics.Science2002297558035335610.1126/science.1072994
    [Google Scholar]
  21. PuzzoD. PiacentiniR. FáM. GulisanoW. LiPuma. D.D.; Staniszewski, A.; Zhang, H.; Tropea, M.R.; Cocco, S.; Palmeri, A.; Fraser, P.; D’Adamio, L.; Grassi, C.; Arancio, O. LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent.eLife20176e2699110.7554/eLife.26991 28696204
    [Google Scholar]
  22. SadegzadehF. SakhaieN. DehghanyR. AdakO. SaadatiH. Effects of adolescent administration of fluoxetine on novel object recognition memory, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor level.Life Sci.202026011833810.1016/j.lfs.2020.118338 32841662
    [Google Scholar]
  23. YukselM. TacalO. Trafficking and proteolytic processing of amyloid precursor protein and secretases in Alzheimer’s disease development: An up-to-date review.Eur. J. Pharmacol.201985617241510.1016/j.ejphar.2019.172415 31132354
    [Google Scholar]
  24. BusciglioJ. GabuzdaD.H. MatsudairaP. YanknerB.A. Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells.Proc. Natl. Acad. Sci. USA19939052092209610.1073/pnas.90.5.2092 8446635
    [Google Scholar]
  25. ChromyB.A. NowakR.J. LambertM.P. ViolaK.L. ChangL. VelascoP.T. JonesB.W. FernandezS.J. LacorP.N. HorowitzP. FinchC.E. KrafftG.A. KleinW.L. Self-assembly of Abeta(1-42) into globular neurotoxins.Biochemistry20034244127491276010.1021/bi030029q 14596589
    [Google Scholar]
  26. NaderipoorP. AmaniM. AbediA. SakhaieN. SadegzadehF. SaadatiH. Alterations in the behavior, cognitive function, and BDNF level in adult male rats following neonatal blockade of GABA-A receptors.Brain Res. Bull.2021169354210.1016/j.brainresbull.2021.01.006 33440220
    [Google Scholar]
  27. GhorbanpourA.M. Combined effects of royal jelly and environmental enrichment against stress-induced cognitive and behavioral alterations in male rats: Behavioral and molecular studies.Nutr. Neurosci.2021112 33814002
    [Google Scholar]
  28. BradfordM.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.Anal. Biochem.1976721-224825410.1016/0003‑2697(76)90527‑3 942051
    [Google Scholar]
  29. SavyC.Y. FitchettA.E. McQuadeR. GartsideS.E. MorrisC.M. BlainP.G. JudgeS.J. Low-level repeated exposure to diazinon and chlorpyrifos decrease anxiety-like behaviour in adult male rats as assessed by marble burying behaviour.Neurotoxicology20155014915610.1016/j.neuro.2015.08.010 26297601
    [Google Scholar]
  30. TerryA.V.Jr GearhartD.A. BeckW.D.Jr TruanJ.N. MiddlemoreM.L. WilliamsonL.N. BartlettM.G. PrendergastM.A. SicklesD.W. BuccafuscoJ.J. Chronic, intermittent exposure to chlorpyrifos in rats: Protracted effects on axonal transport, neurotrophin receptors, cholinergic markers, and information processing.J. Pharmacol. Exp. Ther.200732231117112810.1124/jpet.107.125625 17548533
    [Google Scholar]
  31. FuZ. YangH. XiaoY. ZhaoG. HuangH. The γ-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens.Behav. Brain Funct.2012812010.1186/1744‑9081‑8‑20 22559224
    [Google Scholar]
  32. AldridgeJ.E. LevinE.D. SeidlerF.J. SlotkinT.A. Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression.Environ. Health Perspect.2005113552753110.1289/ehp.7867 15866758
    [Google Scholar]
  33. TimofeevaO.A. RoeggeC.S. SeidlerF.J. SlotkinT.A. LevinE.D. Persistent cognitive alterations in rats after early postnatal exposure to low doses of the organophosphate pesticide, diazinon.Neurotoxicol. Teratol.2008301384510.1016/j.ntt.2007.10.002 18096363
    [Google Scholar]
  34. DarwicheW. Gay-QuéheillardJ. DelanaudS. El Khayat El SabbouriH. KhachfeH. JoumaaW. BachV. RamadanW. Impact of chronic exposure to the pesticide chlorpyrifos on respiratory parameters and sleep apnea in juvenile and adult rats.PLoS One2018131e019123710.1371/journal.pone.0191237 29357379
    [Google Scholar]
  35. BloklandA. Acetylcholine: A neurotransmitter for learning and memory?Brain Res. Brain Res. Rev.199521328530010.1016/0165‑0173(95)00016‑X 8806017
    [Google Scholar]
  36. IvanovićS.R. DimitrijevićB. ĆupićV. JezdimirovićM. BorozanS. SavićM. SavićD. Downregulation of nicotinic and muscarinic receptor function in rats after subchronic exposure to diazinon.Toxicol. Rep.2016352353010.1016/j.toxrep.2016.06.002 28959576
    [Google Scholar]
  37. WuN. WangF. JinZ. ZhangZ. WangL.K. ZhangC. SunT. Effects of GABAB receptors in the insula on recognition memory observed with intellicage.Behav. Brain Funct.2017131710.1186/s12993‑017‑0125‑4 28416021
    [Google Scholar]
  38. NussbaumD. HonarmandK. GovoniR. Kalahani-BargisM. BassS. NiX. LaForgeK. BurdenA. RomeroK. BasarkeS. CourbassonC. DeamondW. An eight component decision-making model for problem gambling: A systems approach to stimulate integrative research.J. Gambl. Stud.201127452356310.1007/s10899‑010‑9219‑8 21191637
    [Google Scholar]
  39. KantamneniS. Cross-talk and regulation between glutamate and GABAB receptors.Front. Cell. Neurosci.2015913510.3389/fncel.2015.00135 25914625
    [Google Scholar]
  40. PousinhaP.A. The amyloid precursor protein C-terminal domain alters CA1 neuron firing, modifying hippocampus oscillations and impairing spatial memory encoding.Cell Rep.201929231733110.1016/j.celrep.2019.08.103
    [Google Scholar]
  41. O’BrienR.J. WongP.C. Amyloid precursor protein processing and Alzheimer’s disease.Annu. Rev. Neurosci.201134118520410.1146/annurev‑neuro‑061010‑113613 21456963
    [Google Scholar]
  42. ElreedyH.A. ElfikyA.M. MahmoudA.A. IbrahimK.S. GhazyM.A. Neuroprotective effect of quercetin through targeting key genes involved in aluminum chloride induced Alzheimer’s disease in rats. Egypt.J. Basic Appl. Sci.202310117418410.1080/2314808X.2022.2164136
    [Google Scholar]
  43. SoneiA. FazelipourS. KanaaniL. JahromyM.H. Protective effects of Berberis vulgaris on diazinon-induced brain damage in young male mice.Prev. Nutr. Food Sci.2020251657010.3746/pnf.2020.25.1.65 32292757
    [Google Scholar]
  44. EssaM.M. SubashS. AkbarM. Al-AdawiS. GuilleminG.J. Long-term dietary supplementation of pomegranates, figs and dates alleviate neuroinflammation in a transgenic mouse model of Alzheimer’s disease.PLoS One2015103e012096410.1371/journal.pone.0120964 25807081
    [Google Scholar]
  45. LeunerK. SchüttT. KurzC. EckertS.H. SchillerC. OcchipintiA. MaiS. JendrachM. EckertG.P. KruseS.E. PalmiterR.D. BrandtU. DröseS. WittigI. WillemM. HaassC. ReichertA.S. MüllerW.E. Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation.Antioxid. Redox Signal.201216121421143310.1089/ars.2011.4173 22229260
    [Google Scholar]
  46. KashyapG. BapatD. DasD. GowaikarR. AmritkarR.E. RangarajanG. RavindranathV. AmbikaG. Synapse loss and progress of Alzheimer’s disease -A network model.Sci. Rep.201991655510.1038/s41598‑019‑43076‑y 31024073
    [Google Scholar]
  47. MoriT. KoyamaN. Guillot-SestierM.V. TanJ. TownT. Ferulic acid is a nutraceutical β-secretase modulator that improves behavioral impairment and alzheimer-like pathology in transgenic mice.PLoS One201382e5577410.1371/journal.pone.0055774 23409038
    [Google Scholar]
  48. Ruiz-MuñozA.M. Nieto-EscamezF.A. AznarS. ColominaM.T. Sanchez-SantedF. Cognitive and histological disturbances after chlorpyrifos exposure and chronic Aβ(1–42) infusions in Wistar rats.Neurotoxicology201132683684410.1016/j.neuro.2011.05.014 21669222
    [Google Scholar]
  49. BakkarR.M. Down’s syndrome with Alzheimer’s disease-like pathology: What can it teach us about the amyloid cascade hypothesis?Int. J. Alzheimers Dis.2010201017581810.4061/2010/175818
    [Google Scholar]
  50. MüllerU.C. DellerT. KorteM. Not just amyloid: Physiological functions of the amyloid precursor protein family.Nat. Rev. Neurosci.201718528129810.1038/nrn.2017.29 28360418
    [Google Scholar]
  51. EnginE. TreitD. The role of hippocampus in anxiety: Intracerebral infusion studies.Behav. Pharmacol.2007185-636537410.1097/FBP.0b013e3282de7929 17762507
    [Google Scholar]
  52. HickM. HerrmannU. WeyerS.W. MallmJ.P. TschäpeJ.A. BorgersM. MerckenM. RothF.C. DraguhnA. SlomiankaL. WolferD.P. KorteM. MüllerU.C. Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity.Acta Neuropathol.20151291213710.1007/s00401‑014‑1368‑x 25432317
    [Google Scholar]
  53. MehrA. HickM. LudewigS. MüllerM. HerrmannU. von EngelhardtJ. WolferD.P. KorteM. MüllerU.C. Lack of APP and APLP2 in GABAergic forebrain neurons impairs synaptic plasticity and cognition.Cereb. Cortex20203074044406310.1093/cercor/bhaa025 32219307
    [Google Scholar]
  54. PalmqvistS. SchöllM. StrandbergO. MattssonN. StomrudE. ZetterbergH. BlennowK. LandauS. JagustW. HanssonO. Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity.Nat. Commun.201781121410.1038/s41467‑017‑01150‑x 29089479
    [Google Scholar]
  55. SalimS. ChughG. AsgharM. Inflammation in anxiety.Adv. Protein Chem. Struct. Biol.20128812510.1016/B978‑0‑12‑398314‑5.00001‑5 22814704
    [Google Scholar]
  56. PerugaI. HartwigS. ThöneJ. HovemannB. GoldR. JuckelG. LinkerR.A. Inflammation modulates anxiety in an animal model of multiple sclerosis.Behav. Brain Res.20112201202910.1016/j.bbr.2011.01.018 21255614
    [Google Scholar]
  57. FourrierC. Bosch-BoujuC. BoursereauR. SauvantJ. AubertA. CapuronL. FerreiraG. LayéS. CastanonN. Brain tumor necrosis factor-α mediates anxiety-like behavior in a mouse model of severe obesity.Brain Behav. Immun.201977253610.1016/j.bbi.2018.11.316 30508579
    [Google Scholar]
  58. FaroukS.M. GadF.A. EmamM.A. Comparative immuno-modulatory effects of basil and sesame seed oils against diazinon-induced toxicity in rats; a focus on TNF-α immunolocalization.Environ. Sci. Pollut. Res. Int.20212855332534610.1007/s11356‑020‑10840‑x 32964385
    [Google Scholar]
  59. HaririA.T. MoallemS.A. MahmoudiM. MemarB. HosseinzadehH. Sub-acute effects of diazinon on biochemical indices and specific biomarkers in rats: Protective effects of crocin and safranal.Food Chem. Toxicol.201048102803280810.1016/j.fct.2010.07.010 20637253
    [Google Scholar]
  60. McDonnellM.A. WangD. KhanS.M. Vander HeidenM.G. KelekarA. Caspase-9 is activated in a cytochrome c-independent manner early during TNFα-induced apoptosis in murine cells.Cell Death Differ.20031091005101510.1038/sj.cdd.4401271 12934075
    [Google Scholar]
  61. RazaviB.M. HosseinzadehH. AbnousK. KhoeiA. ImenshahidiM. Protective effect of crocin against apoptosis induced by subchronic exposure of the rat vascular system to diazinon.Toxicol. Ind. Health20163271237124510.1177/0748233714554941 27353299
    [Google Scholar]
  62. ÁlvarezS. BlancoA. FresnoM. Muñoz-FernándezM.Á. TNF-α contributes to caspase-3 independent apoptosis in neuroblastoma cells: Role of NFAT.PLoS One201161e1610010.1371/journal.pone.0016100 21298033
    [Google Scholar]
  63. McDonnellM.A. AbedinM.J. MelendezM. PlatikanovaT.N. EcklundJ.R. AhmedK. KelekarA. Phosphorylation of murine caspase-9 by the protein kinase casein kinase 2 regulates its cleavage by caspase-8.J. Biol. Chem.200828329201492015810.1074/jbc.M802846200 18467326
    [Google Scholar]
/content/journals/ctmc/10.2174/0115680266363758250306052044
Loading
/content/journals/ctmc/10.2174/0115680266363758250306052044
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test