NAP and D-SAL: neuroprotection against the beta amyloid peptide (1-42).
BACKGROUND
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.


CONCLUSIONS
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.
Gozes
Illana
I
Department of Human Molecular Genetic and Biochemistry, Sackler School of Medicine, Tel Aviv University, Einstein Street, Tel Aviv 69978, Israel. igozes@post.tau.ac.il
Divinski
Inna
I
Piltzer
Inbar
I
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; D014404:Tubulin; C075222:amyloid beta-protein (1-42); C425904:davunetide