The ADNP derived peptide, NAP modulates the tubulin pool: implication for neurotrophic and neuroprotective activities

PLoS One. 2012;7(12):e51458. doi: 10.1371/journal.pone.0051458. Epub 2012 Dec 14.

Abstract

Microtubules (MTs), key cytoskeletal elements in living cells, are critical for axonal transport, synaptic transmission, and maintenance of neuronal morphology. NAP (NAPVSIPQ) is a neuroprotective peptide derived from the essential activity-dependent neuroprotective protein (ADNP). In Alzheimer's disease models, NAP protects against tauopathy and cognitive decline. Here, we show that NAP treatment significantly affected the alpha tubulin tyrosination cycle in the neuronal differentiation model, rat pheochromocytoma (PC12) and in rat cortical astrocytes. The effect on tubulin tyrosination/detyrosination was coupled to increased MT network area (measured in PC12 cells), which is directly related to neurite outgrowth. Tubulin beta3, a marker for neurite outgrowth/neuronal differentiation significantly increased after NAP treatment. In rat cortical neurons, NAP doubled the area of dynamic MT invasion (Tyr-tubulin) into the neuronal growth cone periphery. NAP was previously shown to protect against zinc-induced MT/neurite destruction and neuronal death, here, in PC12 cells, NAP treatment reversed zinc-decreased tau-tubulin-MT interaction and protected against death. NAP effects on the MT pool, coupled with increased tau engagement on compromised MTs imply an important role in neuronal plasticity, protecting against free tau accumulation leading to tauopathy. With tauopathy representing a major pathological hallmark in Alzheimer's disease and related disorders, the current findings provide a mechanistic basis for further development. NAP (davunetide) is in phase 2/3 clinical trial in progressive supranuclear palsy, a disease presenting MT deficiency and tau pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Homeodomain Proteins / chemistry*
  • Humans
  • Mice
  • Microscopy, Confocal / methods
  • NIH 3T3 Cells
  • Nerve Tissue Proteins / chemistry*
  • Neurites / metabolism
  • Neurons / metabolism
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology
  • PC12 Cells
  • Peptides / chemistry
  • Polymers / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Tubulin / chemistry*
  • Tubulin / metabolism
  • Zinc / pharmacology

Substances

  • ADNP protein, rat
  • Adnp protein, mouse
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Oligopeptides
  • Peptides
  • Polymers
  • Tubulin
  • beta3 tubulin, mouse
  • davunetide
  • Zinc

Grant support

Funding was provided by Allon Therapeutics Inc., AMN Foundation, Montreal Circle of Canadian Friends of TAU (CFTAU), Joseph and Grace Alter, Barbara and Donald Seal, the Oberfeld family and the Adams family. Overall, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The valuable input and discussions of the Allon Therapeutics Science Team is appropriately acknowledged.