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To better understand the molecular mechanisms of aging and dementia, it is essential to globally and accurately characterize biomolecules (e.g., proteins) in the brain as a function of age and sex. Here, we present one of the first studies of aging and sexual dimorphism in brains using the zebrafish (\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Danio rerio<\/jats:italic>\n                    <\/jats:styled-content>\n                    ) model, employing mass spectrometry (MS)\u2010based quantitative top\u2010down proteomics (TDP). We analyzed proteoforms in male and female zebrafish brains across three ages (6, 16, and 24\u2009months) using capillary zone electrophoresis\u2010tandem MS (CZE\u2010MS\/MS). We revealed significant sex\u2010 and age\u2010related differences in the abundance of key proteoforms, including those associated with neurofilament assembly, dopaminergic neuron differentiation, and synaptic vesicle priming. Notably, we identified a truncated proteoform of AP2B1, a subunit of the AP2 adaptor complex closely associated with clathrin\u2010mediated endocytosis and cellular aging, in female zebrafish aged 24\u2009months exclusively, suggesting potential age\u2010 and sex\u2010specific roles in brain aging. Additionally, significant changes were observed in proteoforms involved in energy metabolism, structural maintenance, and neurotransmitter release, providing a new opportunity for a better understanding of the molecular mechanisms of brain aging and sexual dimorphism. These findings highlight the effectiveness of CZE\u2010MS\/MS in TDP for identifying and quantifying proteoforms, offering a deep view of sex\u2010specific proteoform dynamics during brain aging.\n                  <\/jats:p>","DOI":"10.1002\/jms.70009","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T08:26:02Z","timestamp":1767083162000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Top\u2010Down Proteomics Study of Aging and Sexual Dimorphism of Zebrafish Brains"],"prefix":"10.1002","volume":"61","author":[{"given":"Mehrdad\u00a0Falamarzi","family":"Askarani","sequence":"first","affiliation":[{"name":"Department of Chemistry Michigan State University  East Lansing Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Poulos","sequence":"additional","affiliation":[{"name":"Department of Animal Science Michigan State University  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