Skip to main content

Advertisement

SpringerLink
Log in

QTC-4-MeOBnE Ameliorated Depressive-Like Behavior and Memory Impairment in 3xTg Mice

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Growing evidence has associated major depressive disorder (MDD) as a risk factor or prodromal syndrome for the occurrence of Alzheimer’s disease (AD). Although this dilemma remains open, it is widely shown that a lifetime history of MDD is correlated with faster progression of AD pathology. Therefore, antidepressant drugs with neuroprotective effects could be an interesting therapeutic conception to target this issue simultaneously. In this sense, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4- carboxamide (QTC-4-MeOBnE) was initially conceived as a multi-target ligand with affinity to β-secretase (BACE), glycogen synthase kinase 3β (GSK3β), and acetylcholinesterase but has also shown secondary effects on pathways involved in neuroinflammation and neurogenesis in preclinical models of AD. Herein, we investigated the effect of QTC-4-MeOBnE (1 mg/kg) administration for 45 days on depressive-like behavior and memory impairment in 3xTg mice, before the pathology is completely established. The treatment with QTC-4-MeOBnE prevented memory impairment and depressive-like behavior assessed by the Y-Maze task and forced swimming test. This effect was associated with the modulation of plural pathways involved in the onset and progression of AD, in cerebral structures of the cortex and hippocampus. Among them, the reduction of amyloid beta (Aβ) production mediated by changes in amyloid precursor protein metabolism and hippocampal tau phosphorylation through the inhibition of kinases. Additionally, QTC-4-MeOBnE also exerted beneficial effects on neuroinflammation and synaptic integrity. Overall, our studies suggest that QTC-4-MeOBnE has a moderate effect in a transgenic model of AD, indicating that perhaps studies regarding the neuropsychiatric effects as a neuroprotective molecule are more prone to be feasible.

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
Fig. 6

Similar content being viewed by others

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Almeida OP, Hankey GJ, Yeap BB, Golledge J, Flicker L (2017) Depression as a modifiable factor to decrease the risk of dementia. Transl Psychiatry 7:e1117. https://doi.org/10.1038/tp.2017.90

    Article  CAS  Google Scholar 

  2. Wiels W, Baeken C, Engelborghs S (2020) Depressive symptoms in the elderly—an early symptom of dementia? A systematic review. Front Pharmacol 11:34. https://doi.org/10.3389/fphar.2020.00034

    Article  Google Scholar 

  3. Green RC, Cupples LA, Kurz A, Auerbach S, Go R, Sadovnick D, Duara R, Kukull WA, Chui H, Edeki T, Griffith PA, Friedland RP, Bachman D, Farrer L (2003) Depression as a risk factor for Alzheimer disease: the MIRAGE study. Arch Neurol 60:753–759. https://doi.org/10.1001/archneur.60.5.753

    Article  Google Scholar 

  4. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D (2006) Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry 63:530–538. https://doi.org/10.1001/archpsyc.63.5.530

    Article  Google Scholar 

  5. Steffens DC (2017) Late-life depression and the prodromes of dementia. JAMA Psychiat 74:673–674. https://doi.org/10.1001/jamapsychiatry.2017.0658

    Article  Google Scholar 

  6. Enache D, Winblad B, Aarsland D (2011) Depression in dementia: epidemiology, mechanisms, and treatment. Curr Opin Psychiatry 24:461–472. https://doi.org/10.1097/YCO.0b013e32834bb9d4

    Article  Google Scholar 

  7. Burke AD, Goldfarb D, Bollam P, Khokher S (2019) Diagnosing and treating depression in patients with Alzheimer’s disease. Neurol Ther 8:325–350. https://doi.org/10.1007/s40120-019-00148-5

    Article  Google Scholar 

  8. Culpepper L, Lam RW, McIntyre RS (2017) Cognitive impairment in patients with depression: awareness, assessment, and management. J Clin Psychiatry 78:1383–1394. https://doi.org/10.4088/JCP.tk16043ah5c

    Article  Google Scholar 

  9. Thompson LI, Jones RN (2020) Depression screening in cognitively normal older adults: measurement bias according to subjective memory decline, brain amyloid burden, cognitive function, and sex. Alzheimer’s Dement (Amsterdam, Netherlands) 12:e12107. https://doi.org/10.1002/dad2.12107

    Article  Google Scholar 

  10. Leonard BE (2007) Inflammation, depression and dementia: are they connected? Neurochem Res 32:1749–1756. https://doi.org/10.1007/s11064-007-9385-y

    Article  CAS  Google Scholar 

  11. Rodrigues R, Petersen RB, Perry G (2014) Parallels between major depressive disorder and Alzheimer’s disease: role of oxidative stress and genetic vulnerability. Cell Mol Neurobiol 34:925–949. https://doi.org/10.1007/s10571-014-0074-5

    Article  CAS  Google Scholar 

  12. Bisht K, Sharma K, Tremblay M-È (2018) Chronic stress as a risk factor for Alzheimer’s disease: roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress, Neurobiol. Stress 9:9–21. https://doi.org/10.1016/j.ynstr.2018.05.003

    Article  Google Scholar 

  13. Berger T, Lee H, Young AH, Aarsland D, Thuret S (2020) Adult hippocampal neurogenesis in major depressive disorder and Alzheimer’s disease. Trends Mol Med 26:803–818. https://doi.org/10.1016/j.molmed.2020.03.010

    Article  Google Scholar 

  14. Babulal GM, Ghoshal N, Head D, Vernon EK, Holtzman DM, Benzinger TLS, Fagan AM, Morris JC, Roe CM (2016) Mood changes in cognitively normal older adults are linked to Alzheimer disease biomarker levels. Am J Geriatr Psychiatry 24:1095–1104. https://doi.org/10.1016/j.jagp.2016.04.004

    Article  Google Scholar 

  15. Donovan NJ, Locascio JJ, Marshall GA, Gatchel J, Hanseeuw BJ, Rentz DM, Johnson KA, Sperling RA (2018) Longitudinal association of amyloid beta and anxious-depressive symptoms in cognitively normal older adults. Am J Psychiatry 175:530–537. https://doi.org/10.1176/appi.ajp.2017.17040442

    Article  Google Scholar 

  16. Chan C, Rosenberg PB (2019) Depression synergy with amyloid and increased risk of cognitive decline in preclinical Alzheimer disease. JAMA Netw Open 2:e198970. https://doi.org/10.1001/jamanetworkopen.2019.8970

    Article  Google Scholar 

  17. Oxtoby NP, Young AL, Cash DM, Benzinger TLS, Fagan AM, Morris JC, Bateman RJ, Fox NC, Schott JM, Alexander DC (2018) Data-driven models of dominantly-inherited Alzheimer’s disease progression. Brain 141:1529–1544. https://doi.org/10.1093/brain/awy050

    Article  Google Scholar 

  18. Al-Harbi KS (2012) Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. https://doi.org/10.2147/PPA.S29716

    Article  Google Scholar 

  19. Li P, Hsiao IT, Liu CY, Chen CH, Huang SY, Yen TC, Wu KY, Lin KJ (2017) Beta-amyloid deposition in patients with major depressive disorder with differing levels of treatment resistance: a pilot study. EJNMMI Res. https://doi.org/10.1186/s13550-017-0273-4

    Article  Google Scholar 

  20. Gatchel JR, Donovan NJ, Locascio JJ, Schultz AP, Becker JA, Chhatwal J, Papp KV, Amariglio RE, Rentz DM, Blacker D, Sperling RA, Johnson KA, Marshall GA (2017) Depressive symptoms and tau accumulation in the inferior temporal lobe and entorhinal cortex in cognitively normal older adults: a pilot study. J Alzheimers Dis 59:975–985. https://doi.org/10.3233/JAD-170001

    Article  CAS  Google Scholar 

  21. Koppel J, Sunday S, Buthorn J, Goldberg T, Davies P, Greenwald B (2013) Elevated CSF tau is associated with psychosis in Alzheimer’s disease. Am J Psychiatry 170:1212–1213. https://doi.org/10.1176/appi.ajp.2013.13040466

    Article  Google Scholar 

  22. Rapp MA, Schnaider-Beeri M, Grossman HT, Sano M, Perl DP, Purohit DP, Gorman JM, Haroutunian V (2006) Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch Gen Psychiatry 63:161–167. https://doi.org/10.1001/archpsyc.63.2.161

    Article  Google Scholar 

  23. Nie L, Wei G, Peng S, Qu Z, Yang Y, Yang Q, Huang X, Liu J, Zhuang Z, Yang X (2017) Melatonin ameliorates anxiety and depression-like behaviors and modulates proteomic changes in triple transgenic mice of Alzheimer’s disease. BioFactors. https://doi.org/10.1002/biof.1369

    Article  Google Scholar 

  24. Luo X, Shui Y, Wang F, Yamamoto R, Kato N (2017) Impaired retention of depression-like behavior in a mouse model of Alzheimer’s disease. IBRO Reports 2:81–86. https://doi.org/10.1016/j.ibror.2017.05.001

    Article  Google Scholar 

  25. Fronza MG, Baldinotti R, Fetter J, Gonçalves Rosa S, Sacramento M, Wayne Nogueira C, Alves D, Praticò D, Savegnago L (2021) Beneficial effects of QTC-4-MeOBnE in an LPS-induced mouse model of depression and cognitive impairments: the role of blood-brain barrier permeability, NF-κB signaling, and microglial activation. Brain Behav Immun. https://doi.org/10.1016/j.bbi.2021.10.002

    Article  Google Scholar 

  26. Fronza MG, Baldinotti R, Fetter J, Sacramento M, Sousa FSS, Seixas FK, Collares T, Alves D, Praticò D, Savegnago L (2020) QTC-4-MeOBnE rescues scopolamine-induced memory deficits in mice by targeting oxidative stress, neuronal plasticity, and apoptosis. ACS Chem Neurosci 11:1259–1269. https://doi.org/10.1021/acschemneuro.9b00661

    Article  CAS  Google Scholar 

  27. Fronza MG, Baldinotti R, Sacramento M, Gutierres J, da CarvalhoFernandes FBMC, Sousa FSS, Seixas FK, Collares T, Alves D, Pratico D, Savegnago L (2021) Effect of QTC-4-MeOBnE treatment on memory, neurodegeneration, and neurogenesis in a streptozotocin-induced mouse model of Alzheimer’s disease. ACS Chem Neurosci 12:109–122

    Article  CAS  Google Scholar 

  28. Fronza MG, Baldinotti R, Martins MC, Goldani B, Dalberto BT, Kremer FS, Begnini K, da Pinto LS, Lenardão EJ, Seixas FK, Collares T, Alves D, Savegnago L (2019) Rational design, cognition and neuropathology evaluation of QTC-4-MeOBnE in a streptozotocin-induced mouse model of sporadic Alzheimer’s disease. Sci Rep 9(1):7276. https://doi.org/10.1038/s41598-019-43532-9

    Article  CAS  Google Scholar 

  29. Fronza MG, Sacramento M, Alves D, Praticò D, Savegnago L (2022) 1-(7-Chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2, 3-triazole-4-carboxamide reduces Aβ formation and tau phosphorylation in cellular models of Alzheimer’s disease. Neurochem Res. https://doi.org/10.1007/s11064-021-03514-8

    Article  Google Scholar 

  30. Spence KW, Lippitt R (1946) An experimental test of the sign-gestalt theory of trial and error learning. J Exp Psychol. https://doi.org/10.1037/h0062419

    Article  Google Scholar 

  31. Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732

    Article  CAS  Google Scholar 

  32. Di Meco A, Li J-G, Blass BE, Abou-Gharbia M, Lauretti E, Praticò D (2017) 12/15-Lipoxygenase inhibition reverses cognitive impairment, brain amyloidosis, and tau pathology by stimulating autophagy in aged triple transgenic mice. Biol Psychiatry 81:92–100. https://doi.org/10.1016/j.biopsych.2016.05.023

    Article  CAS  Google Scholar 

  33. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421. https://doi.org/10.1016/s0896-6273(03)00434-3

    Article  CAS  Google Scholar 

  34. Kitazawa M, Medeiros R, Laferla FM (2012) Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions. Curr Pharm Des 18:1131–1147. https://doi.org/10.2174/138161212799315786

    Article  CAS  Google Scholar 

  35. Baglietto-Vargas D, Prieto GA, Limon A, Forner S, Rodriguez-Ortiz CJ, Ikemura K, Ager RR, Medeiros R, Trujillo-Estrada L, Martini AC, Kitazawa M, Davila JC, Cotman CW, Gutierrez A, LaFerla FM (2018) Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer’s disease. Aging Cell 17:e12791. https://doi.org/10.1111/acel.12791

    Article  CAS  Google Scholar 

  36. Sterniczuk R, Antle MC, Laferla FM, Dyck RH (2010) Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: part 2 Behavioral and cognitive changes. Brain Res 1348:149–155. https://doi.org/10.1016/j.brainres.2010.06.011

    Article  CAS  Google Scholar 

  37. Oh K-J, Perez SE, Lagalwar S, Vana L, Binder L, Mufson EJ (2010) Staging of Alzheimer’s pathology in triple transgenic mice: a light and electron microscopic analysis. Int J Alzheimers Dis 2010(1):24. https://doi.org/10.4061/2010/780102

    Article  Google Scholar 

  38. Belfiore R, Rodin A, Ferreira E, Velazquez R, Branca C, Caccamo A, Oddo S (2019) Temporal and regional progression of Alzheimer’s disease-like pathology in 3xTg-AD mice. Aging Cell 18:e12873. https://doi.org/10.1111/acel.12873

    Article  CAS  Google Scholar 

  39. Beurel E, Grieco SF, Jope RS (2015) Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther 148:114–131. https://doi.org/10.1016/j.pharmthera.2014.11.016

    Article  CAS  Google Scholar 

  40. Fuster-Matanzo A, Llorens-Martín M, Sirerol-Piquer MS, García-Verdugo JM, Avila J, Hernández F (2013) Dual effects of increased glycogen synthase kinase-3β activity on adult neurogenesis. Hum Mol Genet 22:1300–1315. https://doi.org/10.1093/hmg/dds533

    Article  CAS  Google Scholar 

  41. Ahn J, Jang J, Choi J, Lee J, Oh S-H, Lee J, Yoon K, Kim S (2014) GSK3β, but not GSK3α, inhibits the neuronal differentiation of neural progenitor cells as a downstream target of mammalian target of rapamycin complex1. Stem Cells Dev 23:1121–1133. https://doi.org/10.1089/scd.2013.0397

    Article  CAS  Google Scholar 

  42. Mai L, Jope RS, Li X (2002) BDNF-mediated signal transduction is modulated by GSK3beta and mood stabilizing agents. J Neurochem 82:75–83

    Article  CAS  Google Scholar 

  43. Gupta V, Chitranshi N, You Y, Gupta V, Klistorner A, Graham S (2014) Brain derived neurotrophic factor is involved in the regulation of glycogen synthase kinase 3β (GSK3β) signalling. Biochem Biophys Res Commun 454:381–386. https://doi.org/10.1016/j.bbrc.2014.10.087

    Article  CAS  Google Scholar 

  44. Ledo JH, Azevedo EP, Clarke JR, Ribeiro FC, Figueiredo CP, Foguel D, De Felice FG, Ferreira ST (2013) Amyloid-β oligomers link depressive-like behavior and cognitive deficits in mice. Mol Psychiatry 18:1053–1054. https://doi.org/10.1038/mp.2012.168

    Article  CAS  Google Scholar 

  45. Morgese MG, Trabace L (2019) Monoaminergic system modulation in depression and Alzheimer’s disease: a new standpoint? Front Pharmacol 10:483. https://doi.org/10.3389/fphar.2019.00483

    Article  CAS  Google Scholar 

  46. Satir TM, Agholme L, Karlsson A, Karlsson M, Karila P, Illes S, Bergström P, Zetterberg H (2020) Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission. Alzheimer’s Res Ther. https://doi.org/10.1186/s13195-020-00635-0

    Article  Google Scholar 

  47. Baranello R, Bharani K, Padmaraju V, Chopra N, Lahiri D, Greig N, Pappolla M, Sambamurti K (2015) Amyloid-beta protein clearance and degradation (ABCD) Pathways and their role in Alzheimer’s disease. Curr Alzheimer Res. https://doi.org/10.2174/1567205012666141218140953

    Article  Google Scholar 

  48. Yuan X-Z, Sun S, Tan C-C, Yu J-T, Tan L (2017) The role of ADAM10 in Alzheimer’s disease. J Alzheimers Dis 58:303–322. https://doi.org/10.3233/JAD-170061

    Article  Google Scholar 

  49. Hinkle CL, Diestel S, Lieberman J, Maness PF (2006) Metalloprotease-induced ectodomain shedding of neural cell adhesion molecule (NCAM). J Neurobiol 66:1378–1395. https://doi.org/10.1002/neu.20257

    Article  CAS  Google Scholar 

  50. Blundell J, Blaiss CA, Etherton MR, Espinosa F, Tabuchi K, Walz C, Bolliger MF, Südhof TC, Powell CM (2010) Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J Neurosci 30:2115–2129. https://doi.org/10.1523/JNEUROSCI.4517-09.2010

    Article  CAS  Google Scholar 

  51. Klingener M, Chavali M, Singh J, McMillan N, Coomes A, Dempsey PJ, Chen EI, Aguirre A (2014) N-cadherin promotes recruitment and migration of neural progenitor cells from the SVZ neural stem cell niche into demyelinated lesions. J Neurosci 34:9590–9606. https://doi.org/10.1523/JNEUROSCI.3699-13.2014

    Article  CAS  Google Scholar 

  52. Xu J, de Winter F, Farrokhi C, Rockenstein E, Mante M, Adame A, Cook J, Jin X, Masliah E, Lee K-F (2016) Neuregulin 1 improves cognitive deficits and neuropathology in an Alzheimer’s disease model. Sci Rep 6:31692. https://doi.org/10.1038/srep31692

    Article  CAS  Google Scholar 

  53. Bell KFS, Zheng L, Fahrenholz F, Cuello AC (2008) ADAM-10 over-expression increases cortical synaptogenesis. Neurobiol Aging 29:554–565. https://doi.org/10.1016/j.neurobiolaging.2006.11.004

    Article  CAS  Google Scholar 

  54. Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY, Tanzi RE (2013) ADAM10 missense mutations potentiate β-amyloid accumulation by impairing prodomain chaperone function. Neuron 80:385–401. https://doi.org/10.1016/j.neuron.2013.08.035

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by grants from the Conselho Nacional de Pesquisa (CNPq), 430160/2018–6; the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES), PRONEM 16/2551–0000240-1; and the Fundação de Amparo à Pesquisa do Estado do Rio Grande Do Sul (FAPERGS), PqG:17/2551–00011046-9. This study was partially financed by CAPES, finance code 001, but also through CAPES Print, due the exchange period at the Alzheimer’s Center at Temple, Temple University, Philadelphia, PA, done by the first author.

Author information

Authors and Affiliations

  1. Neurobiotechnology Research Group (GPN) – Postgraduate Program of Biotechnology, Federal University of Pelotas (UFPel), Pelotas, RS, Brazil

    Mariana G. Fronza & Lucielli Savegnago

  2. Laboratory of Clean Organic Synthesis (LASOL), Postgraduate Program of Chemistry, UFPel, Pelotas, RS, Brazil

    Manoela Sacramento & Diego Alves

  3. Alzheimer’s Center at Temple – ACT, Temple University, Lewis Katz School of Medicine, Philadelphia, PA, USA

    Domenico Praticò

Authors
  1. Mariana G. Fronza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manoela Sacramento
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diego Alves
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Domenico Praticò
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lucielli Savegnago
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Mariana Fronza, conceptualization, methodology, software data curation, writing—original draft preparation, visualization, and investigation. Manoela Sacrameto, conceptualization and methodology. Diego Alves, conceptualization, methodology, and supervision. Domenico Pratico, conceptualization, methodology, investigation, supervision, and writing—reviewing and editing. Lucielli Savegnago, conceptualization, methodology, investigation, supervision, and writing—reviewing and editing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lucielli Savegnago.

Ethics declarations

Ethics Approval

This study was authorized by the Institutional Animal Care and Usage Committee and conducted in line with the principles of the National Institute of Health guidelines.

Consent to Participate

Not applicable.

Consent for Publication

All authors agreed with the content and gave explicit consent to the formulation and publication of this work.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fronza, M.G., Sacramento, M., Alves, D. et al. QTC-4-MeOBnE Ameliorated Depressive-Like Behavior and Memory Impairment in 3xTg Mice. Mol Neurobiol 60, 1733–1745 (2023). https://doi.org/10.1007/s12035-022-03159-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-03159-w

Keywords

Search

Navigation