NAP Protects against Tau Hyperphosphorylation Through GSK3

Curr Pharm Des. 2018;24(33):3868-3877. doi: 10.2174/1381612824666181112105954.


Background: The most common form of dementia is Alzheimer's disease (AD), which is characterized, in part, by the accumulation of neurofibrillary tangles (NFT), followed by synaptic and neuronal loss. NFTs are mainly composed of aggregated hyperphosphorylated Tau. It has been demonstrated that pathological concentrations of zinc induce 1] activation of a major Tau kinase - the glycogen synthase kinase-3β (GSK-3β), and 2] promote Tau aggregation and toxicity. Activity-dependent neuroprotective protein (ADNP) and its derived peptide NAP exhibit neuroprotective properties against a variety of toxic insults, including toxic zinc concentrations. ADNP deficiency results in increased content of the GSK-3β active form, Tau hyperphosphorylation and NFTlike structure formation, all of which have been prevented by NAP treatment. Our previous experiments showed that NAP enhanced Tau-microtubule association in the face of zinc toxicity. Interestingly, NAP protection against zinc toxicity was rescued by Tau overexpression in NIH-3T3 fibroblast cells, which naturally does not express high amounts of Tau.

Objectives and methods: Pheochromocytoma cells (PC12), exposed to high concentration of zinc (400µM), were used to determine the protective effect of NAP on Tau phosphorylation and two Tau kinases (Fyn and GSK-3β). Knockdown of Tau expression in PC12 cells by RNA silencing was used to determine Tau's requirement for the NAP protective activity under zinc intoxication.

Results: NAP treatment attenuated Tau hyperphosphorylation and GSK-3β increased activity caused by zinc intoxication. Furthermore, Tau knockdown completely abolished NAP protective activity.

Conclusion: These results together with the previous findings strongly corroborated Tau's involvement in NAP/ADNP cellular activity.

Keywords: Activity-dependent neuroprotective protein (ADNP); Alzheimer's disease (AD); Fyn; Glycogen synthase kinase-3β (GSK-3β); NAP; Neurofibrillary tangles (NFT); Tau; Zinc..

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • PC12 Cells
  • Peptides / pharmacology*
  • Phosphorylation / drug effects
  • Protective Agents / pharmacology*
  • Rats
  • tau Proteins / antagonists & inhibitors*
  • tau Proteins / metabolism


  • Peptides
  • Protective Agents
  • tau Proteins
  • Glycogen Synthase Kinase 3 beta