title: D-NAP prophylactic treatment in the SOD mutant mouse model of amyotrophic lateral sclerosis: review of discovery and treatment of tauopathy.
abstract: Davunetide (NAP) is a leading drug candidate being tested against tauopathy. Davunetide is an eight-amino-acid peptide fragment derived by structure-activity studies from activity-dependent neuroprotective protein, activity-dependent neuroprotective protein (ADNP). ADNP is essential for brain formation. ADNP haploinsufficiency in mice results in tauopathy and cognitive deficits ameliorated by davunetide treatment. This article summarizes in brief recent reviews about NAP protection against tauopathy including the all D-amino acid analogue-D-NAP (AL-408). D-NAP was discovered to have similar neuroprotective functions to NAP in vitro. Here, D-NAP was tested as prophylactic as well as therapeutic treatment for amytrophic lateral sclerosis (ALS) in the widely used TgN(SOD1-G93A)1Gur transgenic mouse model. Results showed D-NAP-associated prophylactic protection, thus daily treatment starting from day 2 of age resulted in a prolonged life course in the D-NAP-treated mice, which was coupled to a significant decrease in tau hyperphosphorylation. These studies correlate protection against tau hyperphosphorylation and longevity in a severe model of ALS-like motor impairment and early mortality. NAP is a first-in-class drug candidate/investigation compound providing neuroprotection coupled to inhibition of tau pathology. D-NAP (AL-408) is a pipeline product.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sagol School of Neuroscience, Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jouroukhin
authors.forename: Regina
authors.initials: R
authors.lastname: Ostritsky
authors.forename: Illana
authors.initials: I
authors.lastname: Gozes
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000517:prevention & control*; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D017354:Point Mutation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D024801:Tauopathies / Q000145:classification / Q000188:drug therapy* / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism* / Q000502:physiology
chemical_list: C054369:MAPT protein, human; C558298:Mapt protein, mouse; D018696:Neuroprotective Agents; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; C000606290:SOD1 protein, human; D016875:tau Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C425904:davunetide