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

J Neurosci Res. 2005 Mar 1;79(5):714-23. doi: 10.1002/jnr.20391.


Humanin (HN) is a 24-amino acid peptide that protects neuronal cells from death caused by Alzheimer's disease (AD)-related genes and amyloid-beta (Abeta). 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 Abeta25-35 in mice. The Y-maze test revealed that at least 50 pmol of S14G-HN by intracerebroventricular injection prevented Abeta-induced impairment of short-term/spatial working memory; however, 5 nmol of S14A-HN, a neuroprotection-defective mutant in vitro, did not prevent Abeta-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 Abeta-amnesic mice, indicating that S14G-HN also blocked Abeta-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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amnesia / chemically induced
  • Amnesia / drug therapy
  • Amyloid beta-Peptides / toxicity
  • Analysis of Variance
  • Animals
  • Behavior, Animal
  • Brain / anatomy & histology
  • Brain / metabolism
  • Cell Count / methods
  • Choline O-Acetyltransferase
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Exploratory Behavior / drug effects
  • Genistein / pharmacology
  • Humans
  • Immunohistochemistry / methods
  • Injections, Intraventricular / methods
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Maze Learning / drug effects
  • Memory Disorders / chemically induced
  • Memory Disorders / prevention & control*
  • Memory, Short-Term / drug effects
  • Mice
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / therapeutic use*
  • Proteins / chemistry
  • Proteins / therapeutic use*
  • Reaction Time / drug effects
  • Scopolamine
  • Space Perception / drug effects


  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Neuroprotective Agents
  • Proteins
  • humanin
  • Genistein
  • Scopolamine
  • Choline O-Acetyltransferase