{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T05:21:24Z","timestamp":1766121684969,"version":"3.48.0"},"reference-count":56,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alzheimer\u2019s Disease (AD) is a neurodegenerative disorder characterised by Amyloid-beta 42 (A\u03b242) plaque accumulation and cognitive decline, with current treatments focused on symptomatic relief. Emerging therapeutics, such as dietary interventions, can modulate cognitive decline and delay AD progression. Our previous work in Drosophila melanogaster identified cell competition as a key mechanism that eliminates unfit neurons in an AD model, improving locomotion by removing the unfit neurons expressing flowerLoseB and ahuizotl (azot). Here, we explored how diet influences azot-dependent cell competition and locomotion in the AD model. Flies were fed with either a yeast-based diet (YBD) or a synthetic (SAA) diet for up to 28 days. In contrast to YBD, SAA delayed cell competition activation until day 21, coinciding with locomotion improvement and delayed A\u03b2 formation. The overexpression of the human Flower (hFWE) isoforms in a Drosophila neuronal context revealed functional conservation: hFWE1 acted as the sole loser isoform, and hFWE2 as a winner isoform. With the YBD, forcing cell competition by expressing hFWE2 in the AD model led to an accumulation of unfit cells and promoted worse locomotion phenotypes over time compared to with the SAA diet. Our data highlights the complex interaction between diet, cell competition, and A\u03b2 toxicity, offering new therapeutic insights.<\/jats:p>","DOI":"10.3390\/cells14242011","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T10:41:23Z","timestamp":1765968083000},"page":"2011","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dietary Interventions Modulate Cell Competition and Locomotor Decline in an Alzheimer\u2019s Disease Drosophila Model"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1108-4049","authenticated-orcid":false,"given":"Carolina","family":"Costa-Rodrigues","sequence":"first","affiliation":[{"name":"Champalimaud Centre for the Unknown, Av. Bras\u00edlia, 1400-038 Lisbon, Portugal"}]},{"given":"Jovin R.","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Champalimaud Centre for the Unknown, Av. Bras\u00edlia, 1400-038 Lisbon, Portugal"},{"name":"Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8423-9697","authenticated-orcid":false,"given":"Joana","family":"Couceiro","sequence":"additional","affiliation":[{"name":"Champalimaud Centre for the Unknown, Av. Bras\u00edlia, 1400-038 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4597-7395","authenticated-orcid":false,"given":"Catarina","family":"Br\u00e1s-Pereira","sequence":"additional","affiliation":[{"name":"Champalimaud Centre for the Unknown, Av. Bras\u00edlia, 1400-038 Lisbon, Portugal"},{"name":"Gulbenkian Institute for Molecular Medicine, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5040-452X","authenticated-orcid":false,"given":"Eduardo","family":"Moreno","sequence":"additional","affiliation":[{"name":"Champalimaud Centre for the Unknown, Av. Bras\u00edlia, 1400-038 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"ref_1","unstructured":"Gauthier, S., Rosa-Neto, P., Morais, J., and Webster, C. (2021). World Alzheimer Report 2021: Journey Through the Diagnosis of Dementia, Alzheimer\u2019s Disease International."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bedse, G., Di Domenico, F., Serviddio, G., and Cassano, T. (2015). Aberrant insulin signaling in Alzheimer\u2019s disease: Current knowledge. Front. Neurosci., 9.","DOI":"10.3389\/fnins.2015.00204"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.cell.2015.12.056","article-title":"The Cellular Phase of Alzheimer\u2019s Disease","volume":"164","author":"Karran","year":"2016","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1016\/j.cell.2012.02.040","article-title":"Alzheimer Mechanisms and Therapeutic Strategies","volume":"148","author":"Huang","year":"2012","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1523\/JNEUROSCI.16-14-04491.1996","article-title":"Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer\u2019s Disease","volume":"16","author":"Price","year":"1996","journal-title":"J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41392-024-01911-3","article-title":"Recent advances in Alzheimer\u2019s disease: Mechanisms, clinical trials and new drug development strategies","volume":"9","author":"Zhang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jeon, Y., Lee, J.H., Choi, B., Won, S.Y., and Cho, K.S. (2020). Genetic Dissection of Alzheimer\u2019s Disease Using Drosophila Models. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030884"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1534\/genetics.115.179457","article-title":"Drosophila as an In Vivo Model for Human Neurodegenerative Disease","volume":"201","author":"Mcgurk","year":"2015","journal-title":"Genetics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.nbd.2010.05.026","article-title":"Neurodegenerative models in Drosophila: Polyglutamine disorders, Parkinson disease, and amyotrophic lateral sclerosis","volume":"40","author":"Ambegaokar","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"dmm048926","DOI":"10.1242\/dmm.048926","article-title":"Cell competition from development to neurodegeneration","volume":"14","author":"Couceiro","year":"2021","journal-title":"DMM Dis. Model. Mech."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3390\/ijms10020407","article-title":"Drosophila melanogaster as a model organism of brain diseases","volume":"10","author":"Jeibmann","year":"2009","journal-title":"Int. J. Mol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3661","DOI":"10.1016\/j.celrep.2018.11.098","article-title":"Culling Less Fit Neurons Protects against Amyloid-\u03b2-Induced Brain Damage and Cognitive and Motor Decline","volume":"25","author":"Coelho","year":"2018","journal-title":"Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.3390\/cimb45020098","article-title":"The Quest for Neurodegenerative Disease Treatment\u2014Focusing on Alzheimer\u2019s Disease Personalised Diets","volume":"45","author":"Palimariciuc","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"dev204212","DOI":"10.1242\/dev.204212","article-title":"An expanded view of cell competition","volume":"151","author":"Khandekar","year":"2024","journal-title":"Development"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.tcb.2016.05.009","article-title":"Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer","volume":"26","author":"Merino","year":"2016","journal-title":"Trends Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1038\/s42255-021-00422-7","article-title":"Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development","volume":"3","author":"Lima","year":"2022","journal-title":"Nat. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/s41576-020-0262-8","article-title":"Emerging mechanisms of cell competition","volume":"21","author":"Baker","year":"2020","journal-title":"Nat. Rev. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ydbio.2021.02.011","article-title":"Metabolic regulation of cell competition","volume":"475","author":"Torres","year":"2021","journal-title":"Dev. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41389-023-00505-y","article-title":"Cell competition and cancer from Drosophila to mammals","volume":"13","author":"Cong","year":"2024","journal-title":"Oncogenesis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1146\/annurev-cellbio-111315-125142","article-title":"Cell Competition: Mechanisms and Physiological Roles","volume":"32","author":"Torres","year":"2016","journal-title":"Annu. Rev. Cell Dev. Biol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ceb.2017.10.003","article-title":"Mechanical cell competition","volume":"51","author":"Moreno","year":"2018","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.devcel.2010.09.004","article-title":"Drosophila SPARC is a self-protective signal expressed by loser cells during cell competition","volume":"19","author":"Portela","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.devcel.2010.05.010","article-title":"Flower Forms an Extracellular Code that Reveals the Fitness of a Cell to its Neighbors in Drosophila","volume":"18","author":"Rhiner","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1016\/j.cub.2013.05.053","article-title":"\u201cFitness fingerprints\u201d mediate physiological culling of unwanted neurons in drosophila","volume":"23","author":"Merino","year":"2013","journal-title":"Curr. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.cell.2014.12.017","article-title":"Elimination of Unfit Cells Maintains Tissue Health and Prolongs Lifespan","volume":"160","author":"Merino","year":"2015","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2156735","DOI":"10.1080\/19420889.2022.2156735","article-title":"Azot expression in the Drosophila gut modulates organismal lifespan","volume":"16","author":"Merino","year":"2023","journal-title":"Commun. Integr. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Marques-reis, M., Hauert, B., and Moreno, E. (2024). Longitudinal analysis of Flower-dependent cell competition fitness markers in Drosophila melanogaster. bioRxiv.","DOI":"10.1101\/2024.03.25.586630"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1093\/hmg\/ddr100","article-title":"The ER stress factor XBP1s prevents amyloid-b neurotoxicity","volume":"20","author":"Zhang","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ellouze, I., Sheffler, J., Nagpal, R., and Arjmandi, B. (2023). Dietary Patterns and Alzheimer\u2019s Disease: An Updated Review Linking Nutrition to Neuroscience. Nutrients, 15.","DOI":"10.3390\/nu15143204"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1080\/1028415X.2019.1681088","article-title":"Effect of nutrition on neurodegenerative diseases. A systematic review","volume":"24","author":"Bianchi","year":"2021","journal-title":"Nutr. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1016\/j.celrep.2018.03.104","article-title":"Obesity Suppresses Cell-Competition-Mediated Apical Elimination of RasV12-Transformed Cells from Epithelial Tissues","volume":"23","author":"Sasaki","year":"2018","journal-title":"Cell Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.cell.2013.06.030","article-title":"Transformed drosophila cells evade diet-mediated insulin resistance through wingless signaling","volume":"154","author":"Hirabayashi","year":"2013","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.celrep.2017.06.037","article-title":"Entosis Is Induced by Glucose Starvation","volume":"20","author":"Hamann","year":"2017","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1038\/s41467-018-04167-y","article-title":"P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development","volume":"9","author":"Bowling","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.devcel.2020.04.008","article-title":"Hyperinsulinemia Drives Epithelial Tumorigenesis by Abrogating Cell Competition","volume":"53","author":"Sanaki","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/s41586-019-1429-3","article-title":"Flower isoforms promote competitive growth in cancer","volume":"572","author":"Madan","year":"2019","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.cmet.2017.02.005","article-title":"Matching Dietary Amino Acid Balance to the In Silico-Translated Exome Optimizes Growth and Reproduction without Cost to Lifespan","volume":"25","author":"Piper","year":"2017","journal-title":"Cell Metab."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Colomb, J., Reiter, L., Blaszkiewicz, J., Wessnitzer, J., and Brembs, B. (2012). Open source tracking and analysis of adult Drosophila locomotion in Buridan\u2019s paradigm with and without visual targets. PLoS ONE, 7.","DOI":"10.1371\/annotation\/41b2d3fd-e816-420c-80d0-88290796b1cd"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1038\/s41592-019-0582-9","article-title":"Ilastik: Interactive Machine Learning for (Bio)Image Analysis","volume":"16","author":"Berg","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Han, R., Wei, T.M., Tseng, S.C., and Lo, C.C. (2021). Characterizing approach behavior of Drosophila melanogaster in Buridan\u2019s paradigm. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0245990"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.mad.2006.02.006","article-title":"Differential decline in behavioral performance of Drosophila melanogaster with age","volume":"127","author":"Simon","year":"2006","journal-title":"Mech. Ageing Dev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1016\/j.bbamcr.2011.03.013","article-title":"Interplay between FOXO, TOR, and Akt","volume":"1813","author":"Hay","year":"2011","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kramer, J.M., Davidge, J.T., Lockyer, J.M., and Staveley, B.E. (2003). Expression of Drosophila FOXO regulates growth and can phenocopy starvation. BMC Dev. Biol., 3.","DOI":"10.1186\/1471-213X-3-5"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/nature14684","article-title":"Cell mixing induced by myc is required for competitive tissue invasion and destruction","volume":"524","author":"Levayer","year":"2015","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"625","DOI":"10.3233\/JAD-2011-111505","article-title":"Identification of SPARC-like 1 protein as part of a biomarker panel for Alzheimer\u2019s disease in cerebrospinal fluid","volume":"28","author":"Ball","year":"2012","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e13710","DOI":"10.1111\/cpr.13710","article-title":"Compromised cell competition exhausts neural stem cells pool","volume":"57","author":"Li","year":"2024","journal-title":"Cell Prolif."},{"key":"ref_48","unstructured":"Marques dos Reis, M. (2017). The Role of Neural Death in Alzheimer\u2019s Disease Flower Interacting Candidates in an Amyloid-Beta Model and Exploring a Tau Model in a Cell Competition Context Biological Engineering Examination Committee. [Master\u2019s Thesis, University of Lisbon]."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nrendo.2010.18","article-title":"SPARC: A key player in the pathologies associated with obesity and diabetes","volume":"6","author":"Kos","year":"2010","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_50","unstructured":"Lima, A., Lubatti, G., Burgstaller, J., Hu, D., Green, A., Gregorio, A.D., Zawadzki, T., Pernaute, B., Mahammadov, E., and Dore, M. (2020). Differences in mitochondrial activity trigger cell competition during early mouse development. bioRxiv."},{"key":"ref_51","first-page":"553","article-title":"Flower-deficient mice have reduced susceptibility to skin papilloma formation","volume":"5","author":"Petrova","year":"2012","journal-title":"Dis. Model. Mech."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"101728","DOI":"10.1016\/j.arr.2022.101728","article-title":"Nutrients and amyloid \u03b2 status in the brain: A narrative review","volume":"81","author":"Lengele","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2916","DOI":"10.1016\/j.febslet.2010.05.010","article-title":"Insulin-degrading enzyme antagonizes insulin-dependent tissue growth and Ab-induced neurotoxicity in Drosophila","volume":"584","author":"Tsuda","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1080\/19336934.2021.1915683","article-title":"Characterizing a gene expression toolkit for eye- and photoreceptor-specific expression in Drosophila","volume":"15","author":"Escobedo","year":"2021","journal-title":"Fly"},{"key":"ref_55","first-page":"43","article-title":"GAL4 causes developmental defects and apoptosis when expressed in the developing eye of Drosophila melanogaster","volume":"2","author":"Kramer","year":"2003","journal-title":"Genet. Mol. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"iyad064","DOI":"10.1093\/genetics\/iyad064","article-title":"Visual processing in the fly, from photoreceptors to behavior","volume":"224","author":"Currier","year":"2023","journal-title":"Genetics"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/24\/2011\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T05:11:24Z","timestamp":1766121084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/24\/2011"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":56,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cells14242011"],"URL":"https:\/\/doi.org\/10.3390\/cells14242011","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2025,12,17]]}}}