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Melanoma cell inoculation improves cognitive impairment in the 5xFAD mouse model of Alzheimer’s disease
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  • Published: 27 February 2026

Melanoma cell inoculation improves cognitive impairment in the 5xFAD mouse model of Alzheimer’s disease

  • Bárbara Bruna-Jara1 na1,
  • Jamileth More1 na1,
  • Pedro Lobos1,2,
  • Daniela P. Ponce1,
  • Claudia Duran-Aniotz3,4,
  • José Luis Valdés5,
  • María Alejandra Gleisner6,
  • Fabián Tempio6,
  • Felipe Salech1,5,7,8,9,11,
  • Matías Pizarro3,10,
  • Carol D. SanMartín1,11,12,
  • Martín Cárcamo1,
  • Andrew F. G. Quest6,13,14,
  • Mercedes López2,6,15,
  • Flavio Salazar-Onfray6,16,17 &
  • …
  • María Isabel Behrens1,5,12,18 

Scientific Reports , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer
  • Immunology
  • Neuroscience

Abstract

The inverse association between Alzheimer’s disease (AD) and cancer reported in epidemiological studies remains poorly understood. Five-month-old female and male 5xFAD transgenic AD mice and wildtype (WT) littermate controls were injected with melanoma B16F0 cells or solvent and subsequently monitored for tumor growth and cognitive performance using the Y and Oasis maze for 28 days. Melanoma-inoculated 5xFAD mice (5xFAD/B16F0) demonstrated improved cognition compared to 5xFAD/saline, regardless of tumor development, suggesting a possible contribution of systemic immune modulation rather than a direct effect of tumor growth. 5xFAD/B16F0 mice also showed reduced tumor incidence than WT mice, as well as an increased number of splenic myeloid cells. Although amyloid-β levels and the number of astrocytes and microglia were unchanged, microglial soma area in the hippocampus was reduced in 5xFAD/B16F0 mice, suggesting a shift toward a less reactive microglial morphology. Collectively, these results suggest that peripheral immune changes associated with melanoma inoculation may influence microglial morphology, providing preliminary insights into the potential mechanisms underlying the inverse relationship between AD and cancer.

Data availability

The datasets generated and/or analyzed during the current study were deposited into the University of Chile Research Data Repository and are publicly available as “Melanoma cell inoculation improves cognitive impairment in the 5xFAD mouse model of Alzheimer’s disease” at the following URL: [https://datos.uchile.cl/dataset.xhtml? persistentId=doi:10.34691/UCHILE/UYC3UR](https:/datos.uchile.cl/dataset.xhtml? persistentId=doi:10.34691/UCHILE/UYC3UR).

Abbreviations

4G8:

Anti amyloid-β monoclonal antibody

5xFAD:

Mice bearing five familiar Alzheimer disease linked mutations

Aß:

Amyloid ß peptide

AD:

Alzheimer’s disease

aMCI:

Amnestic mild cognitive impairment

CA1:

Cornus ammonis-1

CA3:

Cornus ammonis-3

CNS:

Central nervous system

DG:

Dentate gyrus

GFAP:

Glial fibrillary acidic protein

Iba1:

Ionized calcium binding adaptor molecule 1

Tg:

Transgenic mice

ThS:

Thioflavin-S

WT:

Wildtype mice

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Acknowledgements

We thank Ximena García, Pamela Contreras, and Ruth Mora for their invaluable help in managing and caring for the animals and Dr Ricardo Bull for valuable help with the analysis of tumor growth.This work was funded by Agencia Nacional de Investigación y Desarrollo de Chile (ANID) FONDECYT Grant numbers 1190958 (MIB), 1170925, 1210644 and 1251598 (AFGQ), 1210622 (CDA); Agencia Nacional de Investigación y Desarrollo de Chile (ANID) FONDECYT Initiation Research Grant number 11190882 (FS); Agencia Nacional de Investigación y Desarrollo de Chile (ANID) Fondecyt Postdoctoral Grant number: 3210806 (JM) and 3240639 (PL); Agencia Nacional de Investigación y Desarrollo de Chile (ANID) Doctoral Scholarship 21210855 (BB) and 21221780 (MP); Agencia Nacional de Investigación y Desarrollo de Chile (ANID) FONDEF Grant numbers ID20I10252 and ID19I10302 (MIB); CONICYT-FONDAP [15130011], FONDAP Continuation project [1523A0008] (AFGQ) and 152220002 (ML); Agencia Nacional de Investigación y Desarrollo de Chile (ANID)/PIA/ANILLOS ACT210096 (CDA); ANID Millennium Science Initiative ICN09_16/ICN 2021_045 (FS-O); U-Redes Universidad de Chile: URC-036/17 (MIB); SEMILLA HCUCH (Hospital Clínico Universidad de Chile) 2022 (CSM). The funders played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.

Funding

This work was funded by Agencia Nacional de Investigación y Desarrollo de Chile (ANID) FONDECYT Grant numbers 1190958 (MIB), 1170925, 1210644 and 1251598 (AFGQ), 1210622 (CDA); Agencia Nacional de Investigación y Desarrollo de Chile (ANID) FONDECYT Initiation Research Grant number 11190882 (FS); Agencia Nacional de Investigación y Desarrollo de Chile (ANID) Fondecyt Postdoctoral Grant number: 3210806 (JM) and 3240639 (PL); Agencia Nacional de Investigación y Desarrollo de Chile (ANID) Doctoral Scholarship 21210855 (BB) and 21221780 (MP); Agencia Nacional de Investigación y Desarrollo de Chile (ANID) FONDEF Grant numbers ID20I10252 and ID19I10302 (MIB); CONICYT-FONDAP [15130011], FONDAP Continuation project [1523A0008] (AFGQ) and 152220002 (ML); Agencia Nacional de Investigación y Desarrollo de Chile (ANID)/PIA/ANILLOS ACT210096 (CDA); ANID Millennium Science Initiative ICN09_16/ICN 2021_045 (FS-O); U-Redes Universidad de Chile: URC-036/17 (MIB); SEMILLA HCUCH (Hospital Clínico Universidad de Chile) 2022 (CSM). The funders played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.

Author information

Author notes

  1. Barbara Bruna-Jara and Jamileth More contributed equally to this work.

Authors and Affiliations

  1. Center for Advanced Clinical Research (CICA), Clinical Hospital of the University of Chile, Av Carlos Lorca Tobar 999, Independencia, Santiago, 8380447, Chile

    Bárbara Bruna-Jara, Jamileth More, Pedro Lobos, Daniela P. Ponce, Felipe Salech, Carol D. SanMartín, Martín Cárcamo & María Isabel Behrens

  2. Interdisciplinary Nucleus of Pharmacology & Immunology Faculty of Medicine, University of Chile, Independencia 1027, Santiago, 8380453, Chile

    Pedro Lobos & Mercedes López

  3. BrainLat Institute (Latin-American Institute of Brain Health), Adolfo Ibáñez University, Av. Diagonal Las Torres 2640, Peñalolén, Santiago, 7911328, Chile

    Claudia Duran-Aniotz & Matías Pizarro

  4. Global Barin Health Institute (GBHI), Dublin, Ireland

    Claudia Duran-Aniotz

  5. Department of Neuroscience, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, 8380453, Chile

    José Luis Valdés, Felipe Salech & María Isabel Behrens

  6. Biomedical Science Institute (ICBM), Faculty of Medicine, University of Chile, Independencia 1027, Santiago, 8380453, Chile

    María Alejandra Gleisner, Fabián Tempio, Andrew F. G. Quest, Mercedes López & Flavio Salazar-Onfray

  7. Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile

    Felipe Salech

  8. Geriatric Service, Department of Internal Medicine, Clinical Hospital of the University of Chile, Av Carlos Lorca Tobar 999, Independencia, Santiago, 8380447, Chile

    Felipe Salech

  9. Geriatric Service, Department of Internal Medicine, German Clinic of Santiago-University of Development, Av Vitacura 5951, Santiago, Chile

    Felipe Salech

  10. Cognitive and Social Neuroscience Center (CSCN), School of Psychology, Adolfo Ibáñez University, Av. Presidente Errázuriz 3485, Las Condes, Santiago, 7550344, Chile

    Matías Pizarro

  11. Institute of Nutrition and Food Technology (INTA), University of Chile, El Líbano 5524, Santiago, 7830490, Chile

    Felipe Salech & Carol D. SanMartín

  12. Department of Neurology and Neurosurgery, Clinical Hospital, University of Chile, Av. Carlos Lorca Tobar 999, Independencia, Santiago, 8380447, Chile

    Carol D. SanMartín & María Isabel Behrens

  13. Laboratory of Cellular Communication, Center for the Study of Exercise, Metabolism and Cancer (CEMC), Interdisciplinary Nucleus of Biology and Genetics, University of Chile, Independencia 1027, Santiago, 8380453, Chile

    Andrew F. G. Quest

  14. Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Independencia 1027, Santiago, 8380453, Chile

    Andrew F. G. Quest

  15. Center for Cancer Prevention and Control (CECAN), Universidad de Chile, Independencia 1027, Santiago, 8380453, Chile

    Mercedes López

  16. Millennium Institute on Immunology and Immunotherapy, University of Chile, Independencia 1027, Santiago, 8380453, Chile

    Flavio Salazar-Onfray

  17. Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Las Palmeras 299, 8320000, Santiago, Chile

    Flavio Salazar-Onfray

  18. Departament of Neurology and Psychiatry, German Clinic of Santiago- University of Development, Av Vitacura 5951, Santiago, 7650568, Chile

    María Isabel Behrens

Authors
  1. Bárbara Bruna-Jara
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  2. Jamileth More
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  3. Pedro Lobos
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  4. Daniela P. Ponce
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  5. Claudia Duran-Aniotz
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  6. José Luis Valdés
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  7. María Alejandra Gleisner
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  8. Fabián Tempio
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  9. Felipe Salech
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  10. Matías Pizarro
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  11. Carol D. SanMartín
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  12. Martín Cárcamo
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  13. Andrew F. G. Quest
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  14. Mercedes López
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  15. Flavio Salazar-Onfray
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  16. María Isabel Behrens
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Contributions

BB performed the experiments, analyzed and interpreted the data regarding the experimental studies of cognitive behavior and neuropathological experiments, and was a major contributor in the writing of the manuscript. JM performed the experiments, analyzed and interpreted the data from cognitive behavior and neuropathological studies, and was a major contributor to the manuscript. DPP managed the experimental design and analyzed and interpreted the results. CDA contributed to the determination of amyloid staining and analyzed and interpreted the data. PL contributed to the analysis and quantification of amyloid plaque staining. AG performed immunological analysis in the brains and spleens of transgenic and WT mice. FT performed immunological analysis on the brains and spleens of transgenic and WT mice. FS contributed to the conceptual design of the study and the analysis of the results. MP contributed to the determination of amyloid staining. CSM contributed with the conceptual design of the study and analysis of the results. MC contributed to the conceptual design of the study and analysis of the results. AFGQ contributed to the conceptual design of the study and analysis of the results, and ML contributed to the analytic discussion of the immunological results. FS-O contributed to the analytic discussion of the immunological results and text revision. MIB contributed to the experimental design, analysis and interpretation of the results and was a major contributor in the writing of the manuscript. All authors read and approved of the final manuscript.

Corresponding author

Correspondence to María Isabel Behrens.

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Cite this article

Bruna-Jara, B., More, J., Lobos, P. et al. Melanoma cell inoculation improves cognitive impairment in the 5xFAD mouse model of Alzheimer’s disease. Sci Rep (2026). https://doi.org/10.1038/s41598-026-40699-w

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  • Received: 27 October 2025

  • Accepted: 16 February 2026

  • Published: 27 February 2026

  • DOI: https://doi.org/10.1038/s41598-026-40699-w

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Keywords

  • Alzheimer’s disease
  • Inverse association between cancer and Alzheimer’s disease
  • 5xFAD mice
  • B16F0 melanoma cells
  • Microglia
  • CXCL10
  • Systemic immune system
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