This review focuses on the discovery of activity-dependent neuroprotective
protein (ADNP) and the ensuing discovery of NAP (
davunetide) toward clinical development with emphasis on microtubule protection. ADNP immunoreactivity was shown to occasionally decorate microtubules and ADNP silencing inhibited neurite outgrowth as measured by
microtubule associated protein 2 (MAP2) labeling. ADNP knockout is lethal, while 50% reduction in ADNP (ADNP haploinsufficiency) resulted in the
microtubule associated protein tau pathology coupled to
cognitive dysfunction and neurodegeneration. NAP (
davunetide), an eight
amino acid peptide derived from ADNP partly ameliorated deficits associated with ADNP deficiency. NAP (
davunetide) interacted with microtubules, protected against microtubule toxicity associated with
zinc,
nocodazole and oxidative stress in vitro and against tau pathology and MAP6 (stable tubuleonly
polypeptide - STOP) pathology in vivo. NAP (
davunetide) provided neurotrophic functions promoting neurite outgrowth as measured by increases in MAP2 immunoreactivity and synapse formation by increasing
synaptophysin expression. NAP (
davunetide) protection against neurodegeneration has recently been shown to extend to
katanin-related microtubule disruption under conditions of tau deficiencies. In conclusion, NAP (
davunetide) provided potent neuroprotection in a broad range of neurodegenerative models, protecting the neuroglial cytoskeleton in vitro and inhibiting tau pathology (
tauopathy) in vivo. Based on these extensive preclinical results,
davunetide (NAP) is now being evaluated in a Phase II/III study of the
tauopathy,
progressive supranuclear palsy (PSP); (Allon
Therapeutics Inc.).