NAP (davunetide) is an eight amino acid peptide (NAPVSIPQ) that has been shown to provide potent neuroprotection, in vitro and in vivo. In human clinical trials, NAP has been shown to increase memory scores in patients suffering from amnestic mild cognitive impairment, a precursor to Alzheimers disease and to enhance functional daily behaviors in schizophrenia patients. NAP is derived from activity-dependent neuroprotective protein (ADNP) a molecule that is essential for brain formation, interacting with the chromatin associated protein alpha and the chromatin remodeling complex SWI/SNF and regulating > 400 genes during embryonic development. Partial loss in ADNP results in cognitive deficits and pathology of the microtubule associated protein tau (tauopathy) that is ameliorated in part by NAP replacement therapy. Recent studies increased the scope of NAP neuroprotection and provided further insights into the NAP mechanisms of action. Thus, it has been hypothesized that the presence of tau on axonal microtubules renders them notably less sensitive to the microtubule-severing protein katanin, and NAP was shown to protect microtubules from katanin disruption in the face of reduced tau expression. Parallel studies showed that NAP reduced the number of apoptotic neurons through activation of PI-3K/Akt pathway in the cortical plate or both PI-3K/Akt and MAPK/MEK1 kinases in the white matter. The interaction of these disparate yet complementary pathways is the subject of future studies towards human brain neuroprotection in the clinical scenario.
Davunetide, NAP, Drug discovery and development, activity-dependent neuroprotective protein (ADNP), neuroprotection, Alzheimer's disease, Parkinson disease, schizophrenia, cognition, behavior, neurodegeneration, developmental disorders, tau, tauopathy, tubulin, microtubules, progressive supranuclear palsy (PSP), frontotemporal dementia, immune interactions, retina, katanin, glutathione, Kainic acid, wortmannin
Department of Human Molecular Genetics and Biochemistry, Tel Aviv University; Tel Aviv 69978, Israel.