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Herein, the current study investigated the possible modulatory effects of memantine\/ rosuvastatin therapy on TGF-\u03b21\/p-Smad\/p21 signaling pathway and their correlation to\u00a0the blood brain barrier transporters involved in A\u03b2-clearance and microRNAs as a novel molecular mechanism in AD treatment. AD was induced by a single intracerebroventricular streptozotocin injection (ICV-STZ, 3 mg\/kg) in rats and drug therapy was continued for 28 days after AD induction. Efficacy was monitored by applying a battery of behavioral assessments, as well as biochemical, histopathological, molecular and gene expression techniques. The upregulated TGF-\u03b21-signaling in the untreated rats was found to be highly correlated to transporters and microRNAs governing A\u03b2-efflux; ABCA1\/miRNA-26 and LRP1\/miRNA-205 expressions, rather than RAGE\/miRNA-185 controlling A\u03b2-influx; an effect that was opposed by the\u00a0tested drugs and was found to be correlated with the abolished TGF-\u03b21-signaling as well. Combined memantine\/rosuvastatin therapy ameliorated the STZ evoked decreases in escape latency and number of crossovers in the Morris water maze test, % spontaneous alternation in the Y-maze test, and discrimination and recognition indices in the object recognition test. The evoked behavioral responses were directly related to the \u03b2-amyloid accumulation and the alteration in its clearance. Additionally, drug treatment increased brain glutathione and decreased malondialdehyde levels. These findings were histopathologically\u00a0confirmed by a marked reduction of gliosis and restoration of neuronal integrity in the CA1 region of the hippocampus of the AD rats. These findings implicated that the memantine\/rosuvastatin combination could offer a new therapeutic potential for AD management by abrogating the TGF-\u03b21\/p-Smad2\/p21 pathway and regulating A\u03b2-clearance.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s11481-024-10159-1","type":"journal-article","created":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T04:53:07Z","timestamp":1734756787000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Memantine\/Rosuvastatin Therapy Abrogates Cognitive and Hippocampal Injury in an Experimental Model of Alzheimer's Disease in Rats: Role of TGF-\u03b21\/Smad Signaling Pathway and Amyloid-\u03b2 Clearance"],"prefix":"10.1007","volume":"20","author":[{"given":"Esraa F.","family":"Zidan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesrine S.","family":"El-Mezayen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safaa H.","family":"Elrewini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elham A.","family":"Afify","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0732-924X","authenticated-orcid":false,"given":"Mennatallah A.","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,21]]},"reference":[{"key":"10159_CR1","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1037\/a0018320","volume":"124","author":"JP Aggleton","year":"2010","unstructured":"Aggleton JP, Albasser MM, Aggleton DJ, Poirier GL, Pearce JM (2010) Lesions of the rat perirhinal cortex spare the acquisition of a complex configural visual discrimination yet impair object recognition. 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