{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:02:55Z","timestamp":1785416575317,"version":"3.56.0"},"reference-count":35,"publisher":"IMR Press","issue":"7","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Program of Fundamental Research in the Russian Federation","award":["FZWG-2026-0003"],"award-info":[{"award-number":["FZWG-2026-0003"]}]},{"name":"Program of Fundamental Research in the Russian Federation","award":["124031800075-1"],"award-info":[{"award-number":["124031800075-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background:Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder leading to dementia, disability, and premature death. Beta-amyloid (A\u03b2) and tau pathology are considered key components of its pathogenesis; however, the role of peripheral amyloid load in modulating pre-existing tau pathology remains understudied. We hypothesized that peripheral amyloid load could exacerbate tau pathology through mechanisms potentially linked to the disruption of the Akt\/glycogen synthase kinase-3\u03b2-associated signaling pathway, which could lead to increased behavioral deficits and progression of neurodegenerative changes.Objective:To evaluate the effect of double peripheral (retro-orbital) administration of the A\u03b2 isoform D7 on the behavioral phenotype, morphological signs of tau pathology, and the expression of genes related to Akt\/GSK-3\u03b2-associated signaling, neuroinflammation, and apoptosis in the brains of P301S transgenic mice.Materials and Methods:The study included 12-week-old male P301S transgenic mice (Tg(Thy1-MAPT*P301S)2541Godt) (n = 20, biological duplication) and wild-type C57Black6\/J mice (n = 10). P301S mice received two retro-orbital injections of isoD7-A\u03b2 into the venous sinus at a dose of 100 \u00b5g (n = 10) with a 1-month interval; control P301S mice received an equivalent volume of water for injection (n = 10). Behavioral testing (\u201copen field\u201d, \u201cnovel object recognition\u201d, \u201cvertical pole\u201d, \u201cinverted screen\u201d) was performed at 16 and 20 weeks of age. Tau pathology was assessed immunohistochemically using AT-8 (pSer202\/pThr205) antibodies in the frontal cortex and brainstem, and amyloid deposits were assessed histologically using Congo red staining in the entorhinal cortex and hippocampus. The expression of Akt1, Gfap, Mapt, Cdk5, Casp3, Bax, and Bcl2 genes in brain tissue was analyzed by quantitative real-time PCR.Results:Two peripheral administrations of isoD7-A\u03b2 were not associated with further deterioration of performance in the \u201copen field\u201d and \u201cnovel object recognition\u201d tests compared to the control P301S group, which likely reflects the already established deficit characteristic of this transgenic line. In contrast, in motor coordination tests (\u201cvertical pole\u201d, \u201cinverted screen\u201d), motor impairments in the P301S+A\u03b2 group emerged by week 16, whereas in P301S mice without amyloid load, they appeared only by week 20. Immunohistochemical analysis revealed an increase in AT-8-positive staining in the brainstem, whereas no statistically significant differences were found between groups in the frontal cortex. Histological analysis did not reveal amyloid plaques in the entorhinal cortex and hippocampus of P301S+A\u03b2 mice and control P301S mice. At the molecular level, the P301S+A\u03b2 group showed decreased Akt1 expression, increased Gfap and Bax expression, and decreased Bcl2 expression, with no significant changes in Mapt, Casp3, and Cdk5. This pattern is consistent with dysregulation of Akt\/GSK-3\u03b2-associated signaling, enhanced glial activation, and a pro-apoptotic shift.Conclusions:Two peripheral administrations of isoD7-A\u03b2 to P301S mice were associated with earlier development of motor impairments, increased tau protein phosphorylation, and changes in gene expression consistent with a disrupted Akt\/GSK-3\u03b2-associated signaling pathway. These findings support the hypothesis that peripheral amyloid load can exacerbate tauopathy manifestations, and the observed transcriptional changes are consistent with the possible involvement of the Akt\/GSK-3\u03b2-associated signaling pathway, which may represent a potential therapeutic target in AD.<\/jats:p>","DOI":"10.31083\/fbl53279","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:17:49Z","timestamp":1785413869000},"source":"Crossref","is-referenced-by-count":0,"title":["Peripheral Administration of isoD7-A\u03b2 Exacerbates Motor Deficits and Tau Pathology in P301S Mice"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7414-7326","authenticated-orcid":true,"given":"Yulia","family":"Stepenko","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, 308015 Belgorod, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0346-9835","authenticated-orcid":true,"given":"Olesya","family":"Shcheblykina","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, 308015 Belgorod, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1969-3615","authenticated-orcid":true,"given":"Nikita","family":"Zhunusov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, 308015 Belgorod, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2941-0241","authenticated-orcid":true,"given":"Veronika","family":"Shmigerova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, 308015 Belgorod, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3018-7932","authenticated-orcid":true,"given":"Sergey","family":"Kozin","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Conformational Polymorphism in Health and Disease, V.A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1517-1983","authenticated-orcid":true,"given":"Vladimir","family":"Mitkevich","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Conformational Polymorphism in Health and Disease, V.A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4554-2116","authenticated-orcid":true,"given":"Alexandra","family":"Radchenko","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, 308015 Belgorod, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2425-5027","authenticated-orcid":true,"given":"Elena","family":"Kuzubova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, 308015 Belgorod, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1715-707X","authenticated-orcid":true,"given":"Leonid","family":"Khalzov","sequence":"additional","affiliation":[{"name":"Faculty of Fundamental Medicine, Pavlov First Saint Petersburg State Medical University, 197022 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5402-0697","authenticated-orcid":true,"given":"Mikhail","family":"Korokin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Belgorod State National Research University, 308015 Belgorod, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref1","unstructured":"World Health Organization. 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