Abstract: 

Neurodegenerative diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), lack effective disease-modifying therapies. Given the complex pathogenic networks driving these disorders, there is an urgent need for novel therapeutic scaffolds. This report investigates the neuroprotective effects and molecular mechanisms of two marine-derived natural products, spectinabilin and chrexanthomycin A (cA), using in vitro cellular assays and in vivo models. In AD models, spectinabilin protected neurons from glutamate and amyloid-beta (Aβ) toxicity and maintained mitochondrial function. It directly inhibited Aβ aggregation and fibril formation. In Caenorhabditis elegans models, spectinabilin reduced Aβ deposition, delayed paralysis, and extended lifespan. Molecular analysis showed that spectinabilin restored presynaptic proteins, such as Rab3A and VAMP2, by modulating the PKA-CREB signaling pathway.  In C9orf72 ALS models, cA acted as a blood-brain barrier-permeable G-quadruplex ligand. In cellular models, cA bound to Nucleolin, reduced toxic RNA foci, and corrected the mislocalization of essential RNA-binding proteins, including Nucleolin and TDP-43. Transcriptomic analysis in ALS mice revealed that cA suppressed disease-associated ribosomal and metabolic stress networks while restoring genes required for axonal guidance and synaptic ion channels. In conclusion, this research demonstrates that marine-derived small molecules provide comprehensive neuroprotection by engaging diverse pathological pathways. Spectinabilin mitigates Aβ toxicity and restores synaptic signaling in AD, while cA targets upstream G-quadruplex structure to alleviate toxicity in ALS. These findings support the use of marine natural products as structural scaffolds for neurodegenerative disease drug discovery.