Yoshikawa_2026_Bioorg.Med.Chem_138_118664

Early Alzheimer's disease (AD) is characterized by extracellular accumulation of amyloid-beta (Abeta) peptides and degeneration of basal forebrain cholinergic neurons. Currently, acetylcholinesterase inhibitors and costly anti-Abeta antibodies are used in clinical practice; however, their therapeutic efficacy remains limited. Consequently, disease-modifying therapies that directly target AD pathogenesis and provide neuroprotection-preferably affordable, small-molecule compounds-are urgently needed. To identify seed compounds with potential for clinical translation, screening platforms that accurately recapitulate AD pathophysiology in human-based models are necessary. Therefore, in this study, we employed previously established human induced pluripotent stem cell-derived basal forebrain cholinergic neurons (hiBFChNs). The inhibitory activity against Abeta aggregation was initially evaluated for 129 natural compounds using the thioflavin T assay. Subsequently, the neuroprotective effects of the 65 selected compounds were assessed in human neuroblastoma SH-SY5Y cells and hiBFChNs using the WST-8 and lactate dehydrogenase assays as secondary and tertiary screening steps, respectively. Among these, 17 compounds demonstrated both inhibitory effects against Abeta aggregation and neuroprotective effects. Further evaluation of physicochemical properties relevant to brain penetration, together with confirmation of in vitro blood-brain barrier (BBB) permeability using a monkey BBB kit, identified daurioxoisoporphine D and moringamine I as promising seed compounds for AD drug development. Overall, these results indicate that a unified screening platform capable of seamlessly evaluating Abeta aggregation inhibition, neuroprotection, and brain permeability could facilitate the identification of small-molecule therapeutics that modify disease progression in AD.