Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β peptide (Aβ) deposition. Aβ accumulation induces oxidative stress, leading to mitochondrial dysfunction, apoptosis, and so forth. Octadecaneuropeptide (ODN), a diazepam-binding inhibitor (DBI)-derived peptide, has been reported to have antioxidant properties. However, it is unclear whether ODN has neuroprotective effects in AD. Objective: To profile the potential effects of ODN on AD. Methods: We established a mouse model of AD via microinjection of Aβ in the lateral ventricle. Utilizing a combination of western blotting assays, electrophysiological recordings, and behavioral tests, we investigated the neuroprotective effects of ODN on AD. Results: DBI expression was decreased in AD model mice and cells. Meanwhile, ODN decreased Aβ generation by downregulating amyloidogenic AβPP processing in HEK-293 cells stably expressing human Swedish mutant APP695 and BACE1 (2EB2). Moreover, ODN could inhibit Aβ-induced oxidative stress in primary cultured cells and mice, as reflected by a dramatic increase in antioxidants and a decrease in pro-oxidants. We also found that ODN could reduce oxidative stress-induced apoptosis by restoring mitochondrial membrane potential, intracellular Ca2 + and cleaved caspase-3 levels in Aβ-treated primary cultured cells and mice. More importantly, intracerebroventricular injection of ODN attenuated cognitive impairments as well as long-term potentiation in Aβ-treated mice. Conclusion: These results suggest that ODN may exert a potent neuroprotective effect against Aβ-induced neurotoxicity and memory decline via its antioxidant effects, indicating that ODN may be a potential therapeutic agent for AD.

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the accumulation of misfolded amyloid-β (Aβ) peptides, which is caused by an imbalance between Aβ production and clearance. Picroside II (Picr II), the principal active constituent of Picrorhizakurroa Royle ex Benth, possesses a range of pharmacological properties, such as anti-inflammatory, antioxidant, and antiapoptotic effects. However, the exact role of Picr II in AD is not yet fully understood. In this study, we investigated the effects of Picr II on AD and found that it inhibited amyloid precursor protein (APP) processing by enhancing autophagy rather than through the ubiquitin-proteasome pathway, resulting in a reduction in Aβ production. Furthermore, Picr II treatment improved the decline in autophagy, which was due not only to an increase in autophagic flux but also to an increase in the fusion of autophagosomes with lysosomes. Most importantly, daily treatment with Picr II (20 mg/kg, i.p.) throughout the experiment rescued the learning and memory in Aβ-treated mice. Taken together, these results suggest that Picr II may have a potent neuroprotective effect against Aβ-induced memory decline by enhancing autophagy, indicating that Picr II may be a promising therapeutic agent for AD.