O2-05-07: Minocycline reduces tau phosphorylation and protects against Aβ-induced neurotoxicity

Abstract

Minocycline is a semi–synthetic, second–generation tetracycline derivative. Recent research has indicated that in addition to its antimicrobial properties, minocycline is also a potent anti–inflammatory, anti–apoptotic and neuroprotective agent when tested in models of neurodegenerative disease. To determine if minocycline may have therapeutic value for the treatment of Alzheimer's disease by preventing tau hyperphosphorylation and amyloid–induced neurotoxicity. We have investigated the effect of minocycline, both in primary neuronal cultures, and in NFT–forming tau transgenic mice (htau line). Treatment of cultures with fibrillar and oligomeric Aβ42 over a period of 48 hours resulted in progressive neuronal death, which was prevented by pre–treatment of cultures with minocycline. Application of minocycline to control cultures also resulted in increased cell survival, demonstrating the neuroprotective properties of this agent. There is increasing evidence to suggest that kinase activation resulting in tau phosphorylation is an important factor in the demise of neurons that results from exposure to Aβ. To investigate this mechanism we have examined the effects of minocycline treatment on pathological tau phosphorylation in response to Aβ in culture, and also during tangle development in htau mice. We find that minocycline treatment results in significantly reduced tau phosphorylation at several epitopes of relevance to AD, including the CP13 and PHF1 epitopes at S202 and S396/404 respectively. The reduced tau phosphorylation we have observed correlates well with decreased cell death following treatment. Furthermore, after minocycline treatment we find reduced activity of specific tau protein kinases, which may account for the decreased tau phosphorylation we have observed. In addition to modulating kinase activities, we find reduced levels of GFAP after minocycline treatment indicating that minocycline can induce suppression of glial responses. These results suggest a dual neuroprotective effect of minocycline with inhibition of kinase activities preventing pathological tau phosphorylation and suppression of glial responses preventing neuroinflammation. At the doses used minocycline is known to be both safe and well tolerated. These results suggest that minocycline may be an effective therapeutic agent for the treatment of Alzheimer's disease and related neurodegenerative disorders. This work was supported by a fellowship grant from the Alzheimer's Society.