Ellagic acid improves the symptoms of early-onset Alzheimer's disease: Behavioral and physiological correlates

<i>Oryza sativa</i> is a globally recognized staple food, rich in essential phyto-phenolic compounds such as γ-Oryzanol (OZ), Ferulic acid (FA), and Ellagic acid (EA). These phytochemicals are known for their potential to beneficially modulate molecular biochemistry. The present investigation aimed to evaluate the neuroprotective and cognitive enhancement effects of <i>Oryza sativa</i> phyto-phenolics in a model of early-onset Alzheimer's disease (EOAD) induced by Aβ (1-42) in animals. <i>In-silico</i> studies suggested that FA, OZ, and EA have target specificity for Aβ, with EA being further selected based on its potent <i>in-vitro</i> Aβ anti-aggregatory effects for exploring neurodegenerative conditions. The <i>in-vivo</i> experiments demonstrated that EA exerts therapeutic effects in Aβ-induced EOAD, modulating both biochemical and behavioral outcomes. EA treatment at two dose levels, EA₇₀ and EA₁₄₀ (70 μM and 140 μM, respectively, administered i.c.v.), significantly counteracted Aβ aggregation and modulated the Ca²⁺/Calpain/GSK-3β/CDK5 signaling pathways, exhibiting anti-tauopathy effects. Additionally, EA was shown to exert anti-inflammatory effects by preventing astroglial activation, modulating FAIM-L expression, and protecting against TNF-α-induced apoptotic signals. Moreover, the neuromodulatory effects of EA were attributed to the regulation of CREB levels, Dnm-1 expression, and synaptophysin levels, thereby enhancing LTP and synaptic plasticity. EA also induced beneficial cytological and behavioral changes, improving both long-term and short-term spatial memory as well as associative learning behavior in the animal model, which underscores its cognitive enhancement properties.