Spectinabilin mitigates Aβ-associated proteotoxic stress and preserves synaptic protein expression in cellular and Caenorhabditis elegans models.

Solubleamyloid-β(Aβ) assemblies, glutamate-associated injury, mitochondrial dysfunction, and synaptic failure are closely connected processes in Alzheimer's disease. Here, we investigated the neuroprotective activity of spectinabilin, a natural product isolated from the marine-derived bacterium Streptomyces spectabilis, using biochemical assays, neuronal cell models, and Caenorhabditis elegans (C. elegans) models of Aβ proteotoxicity. Spectinabilin directly associated with both monomeric and oligomer-enriched FITC-Aβ42 under microscale thermophoresis conditions, with apparent dissociation constants of 13.9 and 2.72 µM, respectively, and reduced the accumulation of ThT-positive β-sheet-rich assemblies and elongated fibrils in vitro. In differentiated HT22 cells and primary cortical neurons, spectinabilin attenuated glutamate- and oligomer-enriched Aβ42-associated reductions in cell viability and preserved mitochondrial membrane potential during Aβ42 exposure. In Aβ-expressing C. elegans, spectinabilin reduced ThS-reactive deposits and oxidative-stress-associated fluorescence, delayed paralysis, extended lifespan, and improved chemotaxis. Integrated transcriptomic analysis showed that spectinabilin partially opposed Aβ-model-associated alterations, particularly in synaptic signaling, G protein-coupled receptor-associated signaling, and membrane-potential-related pathways. Spectinabilin also increased synaptic and cAMP-related transcripts and restored Rab3A and VAMP2 expression while normalizing stress-associated CREB phosphorylation. H89 prevented the recovery of CREB regulation and presynaptic proteins, indicating a requirement for PKA-associated signaling. Together, these findings identify spectinabilin as a marine-derived small-molecule scaffold that modifies Aβ42 assembly and preserves mitochondrial and synaptic homeostasis across cellular and C. elegans models.