Alzheimer’s disease (AD) is a devastating neurodegenerative disease with few available drugs to alleviate, and none to reverse, its pathogenic conditions. Discovery of potential drug candidates is thus a high priority for the field. We have taken steps to enlarge both the methodology and the areas of search for drug candidates by developing an AD-related screen and using it to search for small molecules produced by marine bacteria. We find that even relatively crude extracts of marine bacteria show low toxicity no matter whether they are tested on neuroblastoma cells, on primary cortical neurons or fed orally to live mice. To develop our model system, we have adopted two different approaches. We first mimicked the chronic inflammatory environment of the AD brain by using condit...[ Read more ]

Alzheimer’s disease (AD) is a devastating neurodegenerative disease with few available drugs to alleviate, and none to reverse, its pathogenic conditions. Discovery of potential drug candidates is thus a high priority for the field. We have taken steps to enlarge both the methodology and the areas of search for drug candidates by developing an AD-related screen and using it to search for small molecules produced by marine bacteria. We find that even relatively crude extracts of marine bacteria show low toxicity no matter whether they are tested on neuroblastoma cells, on primary cortical neurons or fed orally to live mice. To develop our model system, we have adopted two different approaches. We first mimicked the chronic inflammatory environment of the AD brain by using conditioned medium (CM) from cultures of THP-1 cells stimulated by fibrillar Aβ. We also followed the AD brain phenotype by directly adding fibrillar Aβ in the neuronal culture. Since neurons are fully differentiated postmitotic cells, we chose the unscheduled activation of neuronal cell cycle events an outcome measure in our evaluation of drug effectiveness. PCSO-524, an extract from green-lipped mussel, was tested and confirmed in both models. It also showed significant neuroprotective effects both in vitro and in vivo. In a more broad-based approach, we screened more than two hundred marine bacterial extracts for their neuroprotective potential by our methods. The most promising extract could not only protect against neuronal cell cycle events, but also preserved synaptic structure in culture. When given orally, extract #16 was able to block the neuronal cell cycle events that precede neurodegeneration in vivo. We believe that both the novel source of natural products we are testing as well as the effective and efficient new screening method will be of significant value in the search for new compounds to fight Alzheimer’s diseases.