Correlation Engine 2.0
Clear Search sequence regions


  • amyloid (8)
  • brain (1)
  • cognition disorders (1)
  • cognitive (3)
  • dementia (1)
  • human (2)
  • impairment (2)
  • inhibit (1)
  • Mapt (1)
  • memory (9)
  • mice (4)
  • p38γ (7)
  • peptides (2)
  • protein precursor (2)
  • signals (1)
  • tau protein (3)
  • Sizes of these terms reflect their relevance to your search.

    Hyperphosphorylation of the neuronal tau protein contributes to Alzheimer's disease (AD) by promoting tau pathology and neuronal and cognitive deficits. In contrast, we have previously shown that site-specific tau phosphorylation can inhibit toxic signals induced by amyloid-β (Aβ) in mouse models. The post-synaptic mitogen-activated protein (MAP) kinase p38γ mediates this site-specific phosphorylation on tau at Threonine-205 (T205). Using a gene therapeutic approach, we draw on this neuroprotective mechanism to improve memory in two -dependent mouse models of AD at stages when advanced memory deficits are present. Increasing activity of post-synaptic kinase p38γ that targets T205 in tau reduced memory deficits in symptomatic -induced AD models. Reconstitution experiments with wildtype human tau or phosphorylation-deficient tauT205A showed that T205 modification is critical for downstream effects of p38γ that prevent memory impairment in APP-transgenic mice. Furthermore, genome editing of the T205 codon in the murine Mapt gene showed that this single side chain in endogenous tau critically modulates memory deficits in APP-transgenic Alzheimer's mice. Ablating the protective effect of p38γ activity by genetic p38γ deletion in a tau transgenic mouse model that expresses non-pathogenic tau rendered tau toxic and resulted in impaired memory function in the absence of human . Thus, we propose that modulating neuronal p38γ activity serves as an intrinsic tau-dependent therapeutic approach to augment compromised cognition in advanced dementia.

    Citation

    Arne Ittner, Prita Riana Asih, Amanda R P Tan, Emmanuel Prikas, Josefine Bertz, Kristie Stefanoska, Yijun Lin, Alexander M Volkerling, Yazi D Ke, Fabien Delerue, Lars M Ittner. Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ. Acta neuropathologica. 2020 Sep;140(3):279-294

    Expand section icon Mesh Tags

    Expand section icon Substances


    PMID: 32725265

    View Full Text