Phytochemical Screening, Molecular Mechanisms and Cognitive Enhancing Potential of Salvia officinalis (Sage) Extracts in Alzheimer's Disease: A Comprehensive In Vivo Analysis of Neuroprotective Pathways

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) accumulation, tau protein hyperphosphorylation, oxidative stress, and neuroinflammation. Current pharmacological treatments provide symptomatic relief but do not halt disease progression. Salvia officinalis (sage), a medicinal herb, has demonstrated cognitive-enhancing and neuroprotective effects in preclinical studies. This study investigates the phytochemical composition, molecular mechanisms, and cognitive effects of Salvia officinalis extracts in an AD model. Methods: Phytochemical screening: High-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) were used to analyze flavonoids, phenolics, and volatile compounds. In vivo study: Rodent AD models were treated with sage extract at different doses. Behavioral tests, including the Morris Water Maze (MWM), Novel Object Recognition (NOR), and Y-maze, were conducted. Biochemical and molecular analysis: Oxidative stress markers (MDA, SOD, CAT, GSH), neuroinflammatory cytokines (TNF-α, IL-6, IL-1β), cholinergic function (AChE inhibition), and BDNF/CREB signaling were evaluated using ELISA, qRT-PCR, and Western blot. Histopathological assessment: Hematoxylin and eosin (H&E) staining and immunohistochemistry were performed to assess neuronal integrity, Aβ deposition, and tau phosphorylation. Results: Phytochemical analysis confirmed the presence of rosmarinic acid, carnosic acid, and essential terpenoids, known for their neuroprotective properties. Sage-treated AD models exhibited improved cognitive function, with significantly better performance in MWM and NOR tests compared to untreated AD models (p < 0.05). Oxidative stress markers were significantly reduced, while antioxidant enzyme activity was elevated (p < 0.01). AChE inhibition and upregulation of BDNF and CREB suggest that sage extract enhances cholinergic neurotransmission and neuroplasticity. Histopathological analysis revealed reduced Aβ plaque deposition and tau phosphorylation, indicating potential disease-modifying effects. Conclusion: The study provides compelling evidence that Salvia officinalis exhibits neuroprotective, antioxidant, and anti-inflammatory properties in an AD model. The observed cognitive improvements and biochemical changes suggest that sage extract could serve as a potential therapeutic agent for AD management. Further clinical trials are necessary to validate its efficacy and safety in humans.