A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice.
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.
Tajima
Hirohisa
H
Department of Pharmacology and Neurosciences, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Kawasumi
Masaoki
M
Chiba
Tomohiro
T
Yamada
Marina
M
Yamashita
Kaoru
K
Nawa
Mikiro
M
Kita
Yoshiko
Y
Kouyama
Keisuke
K
Aiso
Sadakazu
S
Matsuoka
Masaaki
M
Niikura
Takako
T
Nishimoto
Ikuo
I
D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002795:Choline O-Acetyltransferase; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007276:Injections, Intraventricular / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control*; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D011506:Proteins / Q000737:chemistry / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects; D012601:Scopolamine; D013028:Space Perception / Q000187:drug effects
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D011506:Proteins; C427211:humanin; D019833:Genistein; D012601:Scopolamine; D002795:Choline O-Acetyltransferase