A humanin derivative, S14G-HN, prevents amyloid-β-induced memory impairment in mice

Hirohisa Tajima, Masaoki Kawasumi, Tomohiro Chiba, Marina Yamada, Kaoru Yamashita, Mikiro Nawa, Yoshiko Kita, Keisuke Kouyama, Sadakazu Aiso, Masaaki Matsuoka, Takako Niikura, Ikuo Nishimoto

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Abstract

Humanin (HN) is a 24-amino acid peptide that protects neuronal cells from death caused by Alzheimer's disease (AD)-related genes and amyloid-β (Aβ). Multiple studies have revealed its biochemical and neuroprotective characteristics in vitro; however, little has been known regarding whether HN is effective in vivo in AD model systems. We examined the effect of S14G-HN, a 1,000-fold more potent derivative of HN in vitro, on amnesia induced by Aβ25-35 in mice. The Y-maze test revealed that at least 50 pmol of S14G-HN by intracerebroventricular injection prevented Aβ-induced impairment of short-term/spatial working memory; however, 5 nmol of S14A-HN, a neuroprotection-defective mutant in vitro, did not prevent Aβ-induced amnesia. These results are in agreement with the structure-function correlation shown previously in vitro. In the water-finding task, S14G-HN prevented prolongation of finding latency (the time to find water) observed in Aβ-amnesic mice, indicating that S14G-HN also blocked Aβ-induced impairment of latent learning. In accordance with these observations, immunohistochemical analysis showed that S14G-HN sustained the number of cholinergic neurons in the basal forebrain and the striata nearly to the normal level. Furthermore, genistein, a specific inhibitor of tyrosine kinases, blocked recovery from scopolamine-induced amnesia by S14G-HN, suggesting that certain tyrosine kinase(s) are involved in the inhibitory function of S14G-HN in vivo. Taking these findings together, we conclude that S14G-HN has rescue activity against memory impairment caused by AD-related insults in vivo by activating the same intracellular neuroprotective machinery as elucidated previously in vitro.

Original languageEnglish
Pages (from-to)714-723
Number of pages10
JournalJournal of neuroscience research
Volume79
Issue number5
DOIs
Publication statusPublished - 2005 Mar 1

Keywords

  • Alzheimer's disease
  • Humanin
  • Latent learning
  • Neurotoxicity
  • Spatial working memory
  • β-amyloid

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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    Tajima, H., Kawasumi, M., Chiba, T., Yamada, M., Yamashita, K., Nawa, M., Kita, Y., Kouyama, K., Aiso, S., Matsuoka, M., Niikura, T., & Nishimoto, I. (2005). A humanin derivative, S14G-HN, prevents amyloid-β-induced memory impairment in mice. Journal of neuroscience research, 79(5), 714-723. https://doi.org/10.1002/jnr.20391