Abstract
Investigating how glial cells (the major brain cellular population) mediate neuropeptide neuroprotective activity, we have discovered novel neuroprotective proteins. Specifically, we looked at vasoactive intestinal peptide, a major brain regulatory peptide, for its ability to elicit secretion of protective proteins from astrocytes. We have thus identified activity-dependent neurotrophic factor, protecting neurons against electrical blockade. Sequence homology and expression cloning identified activity-dependent neuroprotective protein (ADNP) as a potent neuroprotective protein, with crucial active domains. As a transcription factor, unique to vertebrates and essential for brain formation, Adnp regulates >400 genes, in an age- and sex-dependent manner. ADNP serum expression in humans correlates with cognition, and ADNP mRNA in lymphocytes derived from Alzheimer’s disease patients, is dramatically increased. An innovative approach to compensate for ADNP deficiencies is the ADNP-derived snippet, NAP (NAPVSIPQ) and the 4 amino acid peptide SKIP. NAP (davunetide) is in clinical development, showing efficacy in amnestic mild cognitive impairment patients, at risk for Alzheimer’s disease.
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