Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model

J Pharmacol Exp Ther. 2007 Nov;323(2):438-49. doi: 10.1124/jpet.107.129551. Epub 2007 Aug 24.

Abstract

Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate essential genes. Because complete ADNP deficiency is embryonic lethal, the outcome of partial ADNP deficiency was examined. ADNP(+/-) mice exhibited cognitive deficits, significant increases in phosphorylated tau, tangle-like structures, and neurodegeneration compared with ADNP(+/+) mice. Increased tau hyperphosphorylation is known to cause memory impairments in neurodegenerative diseases associated with tauopathies, including the most prevalent Alzheimer's disease. The current results suggest that ADNP is an essential protein for brain function and plays a role in normal cognitive performance. ADNP-deficient mice offer an ideal paradigm for evaluation of cognitive enhancers. NAP (NAPVSIPQ) is a peptide derived from ADNP that interacts with microtubules and provides potent neuroprotection. NAP treatment partially ameliorated cognitive deficits and reduced tau hyperphosphorylation in the ADNP(+/-) mice. NAP is currently in phase II clinical trials assessing effects on mild cognitive impairment.

Publication types

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

MeSH terms

  • Animals
  • Astrocytes / pathology
  • Cognition Disorders / drug therapy
  • Cognition Disorders / etiology
  • Female
  • Homeodomain Proteins / analysis
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology*
  • Learning / drug effects*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Nerve Tissue Proteins / analysis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Oligopeptides / pharmacology*
  • Oligopeptides / therapeutic use
  • Phosphorylation
  • tau Proteins / metabolism*

Substances

  • Adnp protein, mouse
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • Oligopeptides
  • tau Proteins
  • davunetide