Acta Neuropathologica

, Volume 127, Issue 2, pp 257–270 | Cite as

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

  • Manuela Polydoro
  • Volodymyr I. Dzhala
  • Amy M. Pooler
  • Samantha B. Nicholls
  • A. Patrick McKinney
  • Laura Sanchez
  • Rose Pitstick
  • George A. Carlson
  • Kevin J. Staley
  • Tara L. Spires-Jones
  • Bradley T. Hyman
Original Paper


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.


Tau Arc induction Synaptic dysfunction Alzheimer’s disease 



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.

Supplementary material

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Supplementary material 1 (PPTX 24190 kb)
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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Manuela Polydoro
    • 1
  • Volodymyr I. Dzhala
    • 1
  • Amy M. Pooler
    • 1
    • 2
  • Samantha B. Nicholls
    • 1
  • A. Patrick McKinney
    • 3
  • Laura Sanchez
    • 1
  • Rose Pitstick
    • 4
  • George A. Carlson
    • 4
  • Kevin J. Staley
    • 1
  • Tara L. Spires-Jones
    • 1
  • Bradley T. Hyman
    • 1
  1. 1.Department of Neurology, Massachusetts General HospitalHarvard Medical SchoolCharlestownUSA
  2. 2.Department of Neuroscience, Institute of PsychiatryKing’s College LondonLondonUK
  3. 3.NeuroBehavior Laboratory CoreHarvard NeuroDiscovery CenterBostonUSA
  4. 4.McLaughlin Research InstituteGreat FallsUSA

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