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Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer’s disease model

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Abstract

Neurofibrillary tangles (NFTs), a hallmark of Alzheimer’s disease, are intracellular silver and thioflavin S-staining aggregates that emerge from earlier accumulation of phospho-tau in the soma. Whether soluble misfolded but nonfibrillar tau disrupts neuronal function is unclear. Here we investigate if soluble pathological tau, specifically directed to the entorhinal cortex (EC), can cause behavioral or synaptic deficits. We studied rTgTauEC transgenic mice, in which P301L mutant human tau overexpressed primarily in the EC leads to the development of tau pathology, but only rare NFT at 16 months of age. We show that the early tau lesions are associated with nearly normal performance in contextual fear conditioning, a hippocampal-related behavior task, but more robust changes in neuronal system activation as marked by Arc induction and clear electrophysiological defects in perforant pathway synaptic plasticity. Electrophysiological changes were likely due to a presynaptic deficit and changes in probability of neurotransmitter release. The data presented here support the hypothesis that misfolded and hyperphosphorylated tau can impair neuronal function within the entorhinal-hippocampal network, even prior to frank NFT formation and overt neurodegeneration.

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Acknowledgments

This work was supported by National Institutes of Health grants: R00AG033670, R21AG03885, R01AG026249-07, 5T32AG00022222, American Health Assistance Foundation, the Glenn Foundation, The Alzheimer’s Association Zenith Award ZEN-09-132524, Alzheimer’s Research UK, and a portion of the behavioral work was supported by the Harvard NeuroDiscovery Center. We thank Mark Mayford for providing neuropsin-tTA mice, and Peter Davies for providing tau antibodies.

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Authors and Affiliations

  1. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street Room 2009, Charlestown, MA, 02129, USA

    Manuela Polydoro, Volodymyr I. Dzhala, Amy M. Pooler, Samantha B. Nicholls, Laura Sanchez, Kevin J. Staley, Tara L. Spires-Jones & Bradley T. Hyman

  2. Department of Neuroscience, Institute of Psychiatry, King’s College London, DeCrespigny Park, London, SE5 8AF, UK

    Amy M. Pooler

  3. NeuroBehavior Laboratory Core, Harvard NeuroDiscovery Center, Boston, MA, 02115, USA

    A. Patrick McKinney

  4. McLaughlin Research Institute, Great Falls, MT, 59405, USA

    Rose Pitstick & George A. Carlson

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  1. Manuela Polydoro
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Polydoro, M., Dzhala, V.I., Pooler, A.M. et al. Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer’s disease model. Acta Neuropathol 127, 257–270 (2014). https://doi.org/10.1007/s00401-013-1215-5

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