Neuronal levels and sequence of tau modulate the power of brain rhythms

Melanie Das, Sumihiro Maeda, Bozhong Hu, Gui Qiu Yu, Weikun Guo, Isabel Lopez, Xinxing Yu, Chao Tai, Xin Wang, Lennart Mucke

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Neural network dysfunction may contribute to functional decline and disease progression in neurodegenerative disorders. Diverse lines of evidence suggest that neuronal accumulation of tau promotes network dysfunction and cognitive decline. The A152T-variant of human tau (hTau-A152T) increases the risk of Alzheimer's disease (AD) and several other tauopathies. When overexpressed in neurons of transgenic mice, it causes age-dependent neuronal loss and cognitive decline, as well as non-convulsive epileptic activity, which is also seen in patients with AD. Using intracranial EEG recordings with electrodes implanted over the parietal cortex, we demonstrate that hTau-A152T increases the power of brain oscillations in the 0.5–6 Hz range more than wildtype human tau in transgenic lines with comparable levels of human tau protein in brain, and that genetic ablation of endogenous tau in Mapt−/− mice decreases the power of these oscillations as compared to wildtype controls. Suppression of hTau-A152T production in doxycycline-regulatable transgenic mice reversed their abnormal network activity. Treatment of hTau-A152T mice with the antiepileptic drug levetiracetam also rapidly and persistently reversed their brain dysrhythmia and network hypersynchrony. These findings suggest that both the level and the sequence of tau modulate the power of specific brain oscillations. The potential of EEG spectral changes as a biomarker deserves to be explored in clinical trials of tau-lowering therapeutics. Our results also suggest that levetiracetam treatment is able to counteract tau-dependent neural network dysfunction. Tau reduction and levetiracetam treatment may be of benefit in AD and other conditions associated with brain dysrhythmias and network hypersynchrony.

Original languageEnglish
Pages (from-to)181-188
Number of pages8
JournalNeurobiology of Disease
Volume117
DOIs
Publication statusPublished - 2018 Sep 1

Keywords

  • A152T
  • Alzheimer's disease
  • Biomarker
  • Brain rhythms
  • EEG
  • Epilepsy
  • Levetiracetam
  • Network dysfunction
  • Oscillations
  • Spectrum
  • Tau

ASJC Scopus subject areas

  • Neurology

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  • Cite this

    Das, M., Maeda, S., Hu, B., Yu, G. Q., Guo, W., Lopez, I., Yu, X., Tai, C., Wang, X., & Mucke, L. (2018). Neuronal levels and sequence of tau modulate the power of brain rhythms. Neurobiology of Disease, 117, 181-188. https://doi.org/10.1016/j.nbd.2018.05.020