D-NAP Prophylactic Treatment in the SOD Mutant Mouse Model of Amyotrophic Lateral Sclerosis: Review of Discovery and Treatment of Tauopathy

• Published in: Journal of molecular neuroscience 2012-11, Vol.48 (3), p.597-602
• Main Authors: Jouroukhin, Yan, Ostritsky, Regina, Gozes, Illana
• Format: Article
• Language: English
• Subjects: ADNP protein; Age; Alzheimer's disease; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - prevention & control; Animal models; Animals; Biomedical and Life Sciences; Biomedicine; Brain; Cell Biology; Cognitive ability; D-Amino acids; Disease Models, Animal; Drug development; Drug Evaluation, Preclinical; Female; haploinsufficiency; Humans; Longevity; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mortality; Mutation; Nervous system; Neurochemistry; Neurodegeneration; Neurodegenerative diseases; Neurology; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Oligopeptides - chemistry; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Pathology; Phosphorylation; Phosphorylation - drug effects; Point Mutation; Protein Processing, Post-Translational - drug effects; Proteomics; Recombinant Fusion Proteins - genetics; Reviews; Superoxide dismutase; Superoxide Dismutase - genetics; Superoxide Dismutase-1; Tau protein; tau Proteins - metabolism; tau Proteins - physiology; Tauopathies - classification; Tauopathies - drug therapy; Tauopathies - genetics; Transgenic mice
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1007/s12031-012-9882-6

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.