{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:22:56Z","timestamp":1788909776698,"version":"build-2803163510"},"reference-count":56,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012190","name":"Ministry of Science and Higher Education of the Russian Federation","doi-asserted-by":"publisher","award":["075-15-2025-558"],"award-info":[{"award-number":["075-15-2025-558"]}],"id":[{"id":"10.13039\/501100012190","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Sex-related differences significantly impact biomedical research outcomes, yet female subjects are often excluded due to concerns about variability from the estrous cycle. This study aimed to investigate the sex-dependent differences in behavioral phenotypes and amyloid-beta plaque accumulation in the APPswe\/PS1dE9\/Blg transgenic mouse model of Alzheimer\u2019s disease. Methods: Male and female APPswe\/PS1dE9\/Blg transgenic mice and wild-type (WT) controls were assessed at 7.5 and 10 months of age. A comprehensive behavioral test battery was employed, including the Open Field, Novel Object Recognition, Y-Maze, and Barnes Maze tests. Histological analysis of amyloid plaque was carried out. Results: Female transgenic mice displayed delayed accumulation of A\u03b2 plaques and milder cognitive decline compared with males. At 10 months, plaque load in females corresponded to that of 7.5-month-old males, demonstrating a temporal lag in pathology. Behavioral impairments correlated negatively with cortical plaque burden (r = \u22120.4964, p = 0.0181), supporting its role as a structural biomarker of disease progression. Conclusions: This study identifies distinct sex-dependent trajectories of behavioral and histomorphometric biomarkers in APPswe\/PS1dE9\/Blg mice. Females exhibit delayed amyloid pathology and cognitive decline, suggesting intrinsic neuroprotective mechanisms that modulate biomarker expression over time. These findings emphasize the necessity of integrating both sexes in preclinical biomarker research and support the use of morphometric endpoints as translationally relevant indicators of Alzheimer\u2019s disease progression.<\/jats:p>","DOI":"10.3390\/brainsci15111237","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T11:05:31Z","timestamp":1763463931000},"page":"1237","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sex-Dependent Phenotypic and Histomorphometric Biomarkers in the APPswe\/PS1dE9\/Blg Mouse Model of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"given":"Elena","family":"Kuzubova","sequence":"first","affiliation":[{"name":"Research Institute of Pharmacology of Living Systems, Belgorod State National Research University, 85 Pobedy St., Belgorod 308015, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Radchenko","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmacology of Living Systems, Belgorod State National Research University, 85 Pobedy St., Belgorod 308015, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail","family":"Pokrovskii","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmacology of Living Systems, Belgorod State National Research University, 85 Pobedy St., Belgorod 308015, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0346-9835","authenticated-orcid":false,"given":"Olesya","family":"Shcheblykina","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmacology of Living Systems, Belgorod State National Research University, 85 Pobedy St., Belgorod 308015, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0258-1879","authenticated-orcid":false,"given":"Kirill","family":"Chaprov","sequence":"additional","affiliation":[{"name":"Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 119071, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3822-4213","authenticated-orcid":false,"given":"Arkadii","family":"Nesterov","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmacology of Living Systems, Belgorod State National Research University, 85 Pobedy St., Belgorod 308015, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Avtina","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmacology of Living Systems, Belgorod State National Research University, 85 Pobedy St., Belgorod 308015, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Pokrovskii","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmacology of Living Systems, Belgorod State National Research University, 85 Pobedy St., Belgorod 308015, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5402-0697","authenticated-orcid":false,"given":"Mikhail","family":"Korokin","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmacology of Living Systems, Belgorod State National Research University, 85 Pobedy St., Belgorod 308015, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3298","DOI":"10.1093\/brain\/aws259","article-title":"Interleukin 6-Preconditioned Neural Stem Cells Reduce Ischaemic Injury in Stroke Mice","volume":"135","author":"Sakata","year":"2012","journal-title":"Brain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1002\/stem.1632","article-title":"Interleukin 6 Mediates the Therapeutic Effects of Adipose-Derived Stromal\/Stem Cells in Lipopolysaccharide-Induced Acute Lung Injury","volume":"32","author":"Zhang","year":"2014","journal-title":"Stem Cells"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1111\/cns.13280","article-title":"Neuro-Cells Therapy Improves Motor Outcomes and Suppresses Inflammation during Experimental Syndrome of Amyotrophic Lateral Sclerosis in Mice","volume":"26","author":"Shafarevich","year":"2020","journal-title":"CNS Neurosci. 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