Caniferolide A, a Macrolide from Streptomyces caniferus, Attenuates Neuroinflammation, Oxidative Stress, Amyloid-Beta, and Tau Pathology in Vitro.

The macrolide caniferolide A was isolated from extracts of a culture of the marine-derived actinomycete Streptomyces caniferus, and its ability to ameliorate Alzheimer's disease (AD) hallmarks was determined. The compound reduced neuroinflammatory markers in BV2 microglial cells activated with lipopolysaccharide (LPS), being able to block NFκB-p65 translocation to the nucleus and to activate the Nrf2 pathway. It also produced a decrease in pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), reactive oxygen species (ROS) and nitric oxide release and inhibited iNOS, JNK, and p38 activities. Moreover, the compound blocked BACE1 activity and attenuated Aβ-activation of microglia by drastically diminishing ROS levels. The phosphorylated state of the tau protein was evaluated in SH-SY5Y tau441 cells. Caniferolide A reduced Thr212 and Ser214 phosphorylation by targeting p38 and JNK MAPK kinases. On the other side, the antioxidant properties of the macrolide were determined in an oxidative stress model with SH-SY5Y cells treated with H