Tau pathology-mediated presynaptic dysfunction

Neuroscience. 2016 Jun 14;325:30-8. doi: 10.1016/j.neuroscience.2016.03.044. Epub 2016 Mar 21.

Abstract

Brain tauopathies are characterized by abnormal processing of tau protein. While somatodendritic tau mislocalization has attracted considerable attention in tauopathies, the role of tau pathology in axonal transport, connectivity and related dysfunctions remains obscure. We have previously shown using the squid giant synapse that presynaptic microinjection of recombinant human tau protein (htau42) results in failure of synaptic transmission. Here, we evaluated molecular mechanisms mediating this effect. Thus, the initial event, observed after htau42 presynaptic injection, was an increase in transmitter release. This event was mediated by calcium release from intracellular stores and was followed by a reduction in evoked transmitter release. The effect of htau42 on synaptic transmission was recapitulated by a peptide comprising the phosphatase-activating domain of tau, suggesting activation of phosphotransferases. Accordingly, findings indicated that htau42-mediated toxicity involves the activities of both GSK3 and Cdk5 kinases.

Keywords: Cdk5; GSK3; IP3 receptor; phosphatase-activating domain of tau; ryanodine receptor; tauopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Calcium / metabolism
  • Cyclin-Dependent Kinase 5 / metabolism
  • Decapodiformes
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Presynaptic Terminals / drug effects*
  • Presynaptic Terminals / metabolism*
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • Synaptic Transmission / drug effects*
  • tau Proteins / toxicity*

Substances

  • Inositol 1,4,5-Trisphosphate Receptors
  • MAPT protein, human
  • Ryanodine Receptor Calcium Release Channel
  • tau Proteins
  • Cyclin-Dependent Kinase 5
  • Glycogen Synthase Kinase 3 beta
  • Calcium