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Tau Phosphorylation and Cleavage in Ethanol-Induced Neurodegeneration in the Developing Mouse Brain

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Abstract

Previous studies indicated that ethanol-induced neurodegeneration in postnatal day 7 (P7) mice, widely used as a model for the fetal alcohol spectrum disorders, was accompanied by glycogen synthase kinase-3β (GSK-3β) and caspase-3 activation. Presently, we examined whether tau, a microtubule associated protein, is modified by GSK-3β and caspase-3 in ethanol-treated P7 mouse forebrains. We found that ethanol increased phosphorylated tau recognized by the paired helical filament (PHF)-1 antibody and by the antibody against tau phosphorylated at Ser199. Ethanol also generated tau fragments recognized by an antibody against caspase-cleaved tau (C-tau). C-tau was localized in neurons bearing activated caspase-3 and fragmented nuclei. Over time, cell debris and degenerated projections containing C-tau appeared to be engulfed by activated microglia. A caspase-3 inhibitor partially blocked C-tau formation. Lithium, a GSK-3β inhibitor, blocked ethanol-induced caspase-3 activation, phosphorylated tau elevation, C-tau formation, and microglial activation. These results indicate that tau is phosphorylated by GSK-3β and cleaved by caspase-3 during ethanol-induced neurodegeneration in the developing brain.

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Acknowledgments

We thank Dr. Peter Davies (Albert Einstein College of Medicine, New York, NY) for providing the PHF-1 antibody. This work was supported by National Institute on Alcohol Abuse and Alcoholism grant AA015355.

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Authors and Affiliations

  1. Laboratory of Neurobehavior Genetics, The Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY, 10962, USA

    Mariko Saito, Goutam Chakraborty, Rui-Fen Mao, Sun-Mee Paik & Csaba Vadasz

  2. Division of Analytical Psychopharmacology, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    Mitsuo Saito

  3. Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA

    Mariko Saito, Csaba Vadasz & Mitsuo Saito

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  1. Mariko Saito
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Correspondence to Mariko Saito.

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Saito, M., Chakraborty, G., Mao, RF. et al. Tau Phosphorylation and Cleavage in Ethanol-Induced Neurodegeneration in the Developing Mouse Brain. Neurochem Res 35, 651–659 (2010). https://doi.org/10.1007/s11064-009-0116-4

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