Memantine/Rosuvastatin Therapy Abrogates Cognitive and Hippocampal Injury in an Experimental Model of Alzheimer's Disease in Rats: Role of TGF-β1/Smad Signaling Pathway and Amyloid-β Clearance

• Published in: Journal of neuroimmune pharmacology 2024-12, Vol.20 (1), p.4
• Main Authors: Zidan, Esraa F., El-Mezayen, Nesrine S., Elrewini, Safaa H., Afify, Elham A., Ali, Mennatallah A.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - metabolism; Disease Models, Animal; Hippocampus - drug effects; Hippocampus - metabolism; Immunology; Male; Maze Learning - drug effects; Memantine - pharmacology; Memantine - therapeutic use; MicroRNAs; Neurosciences; Pharmacology/Toxicology; Rats; Rats, Wistar; Rosuvastatin Calcium - pharmacology; Rosuvastatin Calcium - therapeutic use; Signal Transduction - drug effects; Smad Proteins - metabolism; Transforming Growth Factor beta1 - metabolism; Virology
• ISSN: 1557-1890; 1557-1904; 1557-1904
• DOI: 10.1007/s11481-024-10159-1

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder of complex pathogenesis and multiple interacting signaling pathways where amyloidal-β protein (Aβ) clearance plays a crucial role in cognitive decline. Herein, the current study investigated the possible modulatory effects of memantine/ rosuvastatin therapy on TGF-β1/p-Smad/p21 signaling pathway and their correlation to the blood brain barrier transporters involved in Aβ-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-β1-signaling in the untreated rats was found to be highly correlated to transporters and microRNAs governing Aβ-efflux; ABCA1/miRNA-26 and LRP1/miRNA-205 expressions, rather than RAGE/miRNA-185 controlling Aβ-influx; an effect that was opposed by the tested drugs and was found to be correlated with the abolished TGF-β1-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 β-amyloid accumulation and the alteration in its clearance. Additionally, drug treatment increased brain glutathione and decreased malondialdehyde levels. These findings were histopathologically confirmed 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-β1/p-Smad2/p21 pathway and regulating Aβ-clearance. Graphical Abstract