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Minocycline reduces the development of abnormal tau species in models of Alzheimer’s disease

Wendy Noble^*,1, Claire Garwood^*, John Stephenson^*, Anna M. Kinsey, Diane P. Hanger^* and Brian H. Anderton^*

^* Department of Neuroscience and

Division of Old Age Psychiatry, MRC Centre for Neurodegeneration Research, King’s College London, Institute of Psychiatry, London, UK

¹Correspondence: MRC Centre for Neurodegeneration Research, King’s College London, Institute of Psychiatry, Department of Neuroscience, PO37, De Crespigny Park, London, SE5 8AF, UK. E-mail: wendy.noble{at}iop.kcl.ac.uk

Alzheimer’s disease (AD) is characterized by the presence of neurofibrillary tangles of hyperphosphorylated, aggregated tau protein and extracellular deposits of β-amyloid peptide. Increased β-amyloid levels are thought to precede tangle formation, but tau pathology is more closely related to neuronal death. Minocycline, a tetracycline derivative, has potent antiinflammatory, antiapoptotic, and neuroprotective effects in several models of neurodegenerative disease, including models of AD with amyloid pathology. We have used both in vitro and in vivo models of AD to determine whether minocycline may have therapeutic efficacy against tau pathology. In primary cortical neurons, minocycline prevents β-amyloid-induced neuronal death, reduces caspase-3 activation, and lowers generation of caspase-3-cleaved tau fragments. Treatment of tangle-forming transgenic mice (htau line) with minocycline results in reduced levels of tau phosphorylation and insoluble tau aggregates. The in vivo effects of minocycline are also associated with reduced caspase-3 activation and lowered tau cleavage by caspase-3. In tau mice, we find that conformational changes in tau are susceptible to minocycline treatment, but are not directly associated with the amount of tau fragments produced, highlighting a dissociation between the development of these pathological tau species. These results suggest a possible novel therapeutic role for minocycline in the treatment of AD and related tauopathies.—Noble, W., Garwood, C., Stephenson, J., Kinsey, A. M., Hanger, D. P., Anderton, B. H. Minocycline reduces the development of abnormal tau species in models of Alzheimer’s disease.

Key Words: caspase-3 • therapeutic • neurodegeneration • tauopathy • β-amyloid