NAP and D-SAL: neuroprotection against the β amyloid peptide (1-42)

Introduction: NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln, single amino acid letter code, NAPVSIPQ), an eight amino acid neuroprotective peptide derived from activity-dependent neuroprotective protein (ADNP), exhibits some structural similarity to activity-dependent neurotropic factor-9 (ADNF-9; Ser-Alal-Leu-Leu-Arg-Ser-Ile-Pro-Ala, SALLRSIPA). Both peptides are also active in the all D-amino acid conformation, termed D-NAP and D-SAL. Original results utilizing affinity chromatography coupled to mass spectrometry identified tubulin, the subunit protein of microtubules, as the major NAP-associating protein in brain. The NAP-tubulin association was found to be diminished in the presence of ADNF-9, D-NAP, and D-SAL, suggesting a common target of neuroprotection. The beta amyloid peptide interacts with microtubules, and previous studies have demonstrated protection against beta amyloid (25-35) toxicity by NAP and ADNF-9. NAP also inhibits beta amyloid (25-35 and 1-40) aggregation. Methods: Cerebral cortical cultures derived from newborn rats were used in neuronal survival assays to test the activity of both NAP and D-SAL against the major Alzheimer's disease toxic peptide beta amyloid (1-42). Results: NAP and D-SAL protected cerebral cortical neurons against the major Alzheimer's disease toxic peptide beta amyloid (1-42). Maximal protection of both peptides was observed at concentrations of 10(-15) to 10(-10) mol/l. Conclusion: These findings, together with those of previous in vivo studies conducted in relevant Alzheimer's disease models, pave the path to drug development. Bioavailability studies indicated that NAP penetrates cells and crosses the blood-brain barrier after nasal or systemic administration. Phase II clinical trials of NAP are currently in progress by Allon Therapeutics Inc.