DR. SHANKAR CHINTA

Pharmacological Attenuation of Abeta (Aβ) Oligomer Mediated Microglial NLRP3 Inflammasome Activation

The link between amyloid deposition and neurofibrillary tangle formation is critical for Alzheimer’s pathogenesis and drug development. Recent studies have suggested a protein complex NLRP3 inflammasome (NOD-Like Receptor family, Pyrin domain containing 3) links these hallmarks, and further inhibition of NLRP3 could largely protect from memory loss and decrease Aβ deposition in AD transgenic mouse model. This key role of the NLRP3 inflammasome in Aβ and tau-mediated inflammatory responses suggests that therapeutics that blocks the activity of the NLRP3 inflammasome or downstream inflammasome-derived cytokines could potentially represent a novel therapeutic target for AD.
With this rationale, using a high-throughput screen in cultured microglia, we successfully identified a series of small-molecule inhibitors of NLRP3-mediated caspase-1 formation. One of the most effective was nordihydroguiateric acid (NDGA), a potent antioxidant found in the leaf extracts of Larrea tridentata, a plant known to increase lifespan in mammals. Our preliminary data murine microglia (IMG cells) demonstrates that NDGA dose-dependently attenuates the Aβ- and tau-mediated induction of the pro- inflammatory IL1-β and IL-18, in conjunction with suppression of NLRP3 activation, indicating potent anti- inflammatory properties. Mechanistically, this appears to involve the induction of a cytosolic deacetylase enzyme, Sirtuin 2 (SIRT2). Currently, we are in the process of testing the therapeutic potential of NDGA using a well-established in vivo model of Abeta/tau-induced neuropathology, the 3xAD mouse model.