Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorder of the central nervous system, characterized by memory loss and cognitive decline. The two main hypotheses regarding AD involve the accumulation of amyloid-β (Aβ) forming plaques and the intracellular hyperphosphorylation of tau protein, leading to the formation of neurofibrillary tangles (NFT). These processes are accompanied by neuroinflammation and oxidative stress, and eventual neuronal death. While soy foods are widely recognized for their nutritional benefits, soybean pulp (okara), the residue left over from making tofu or soybean milk, is mostly discarded as kitchen waste, despite being rich in nutrients such as dietary fiber, protein, and isoflavones. This underutilized byproduct may serve as a valuable resource for functional food development and sustainable resource use. In this study, fermented soybean pulp (FS) demonstrated neuroprotective effects. In vitro, FS at concentrations of 0.001 µg/mL and 0.01 µg/mL significantly improved cell viability in Aβ-induced HT-22 cells and reduced lipid peroxidation. Further, in vivo oral administration of FS attenuated the cognitive deficits of 5 × FAD mice, enhancing both short and long-term memory and reducing anxiety-like behaviors. Immunohistochemical analysis revealed that the FS-treated 5 × FAD mice group significantly reduced hippocampal amyloid plaque accumulation and gliosis. FS also upregulated the expression levels of brain-derived neurotrophic factor (BDNF), PSD95, and synaptophysin, while preventing hippocampal neuronal loss. Mechanistically, FS may activate the Nrf2 antioxidant pathway and NF-κB-mediated inflammation through the modulation of the Akt/GSK3β signaling axis in the hippocampus. These molecular actions likely contribute to increased antioxidant enzymes and suppressed neuroinflammatory responses. Overall, this study suggests that FS has therapeutic potential for alleviating cognitive and behavioral impairments in AD. Moreover, the repurposing of soybean pulp, which would otherwise be discarded, enhances its utilization value and supports sustainable green recycling.