Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in a transgenic mouse model of Alzheimer's disease at early pathological stage

• Published in: Journal of molecular neuroscience Vol. 31; no. 2; pp. 165 - 170
• Main Authors: Matsuoka, Yasuji, Gray, Audrey J, Hirata-Fukae, Chiho, Minami, S Sakura, Waterhouse, Emily Graeme, Mattson, Mark P, LaFerla, Frank M, Gozes, Illana, Aisen, Paul S
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 01-06-2007
• Subjects: Accumulation; Administration, Intranasal; Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Animal models; Animals; Binding; Brain; Chemical compounds; Disease Models, Animal; Health services; Humans; In vivo methods and tests; Mice; Mice, Transgenic; Microtubules; Neurodegenerative diseases; Neuroprotection; Neurotoxicity; Oligopeptides - administration & dosage; Oligopeptides - therapeutic use; Pathology; Peptides - genetics; Peptides - metabolism; Pharmacology; Phosphorylation; Rodents; Tau protein; tau Proteins - metabolism; Threonine; Transgenic animals; Transgenic mice; Tubulin; β-Amyloid
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1385/jmn/31:02:165

Accumulation of beta-amyloid (Abeta) peptide and hyperphosphorylation of tau in the brain are pathological hallmarks of Alzheimer's disease (AD). Agents altering these pathological events might modify clinical disease progression. NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) is an octapeptide that has shown neuroprotective effects in various in vitro and in vivo neurodegenerative models. Previous studies showed that NAP protected against Abeta-induced neurotoxicity, inhibited Abeta aggregation, and, by binding to tubulin, prevented disruption of microtubules. In this study, we investigated the effect of NAP on Abeta and tau pathology using a transgenic mouse model that recapitulates both aspects of AD. We administered NAP intranasally (0.5 microg/mouse per day, daily from Monday through Friday) for 3 mo, starting from 9 mo of age, which is a prepathological stage in these mice. NAP treatment significantly lowered levels of Abeta 1-40 and 1-42 in brain. In addition, NAP significantly reduced levels of hyperphosphorylated tau. Of particular interest, hyperphosphorylation at the threonine 231 site was reduced; phosphorylation at this site influences microtubule binding. Our results indicate that NAP treatment of transgenic mice initiated at an early stage reduced both Abeta and tau pathology, suggesting that NAP might be a potential therapeutic agent for AD.