Nasal Colivelin treatment ameliorates memory impairment related to Alzheimer's disease.
Humanin (HN) and its derivatives, such as Colivelin (CLN), suppress neuronal death induced by insults related to Alzheimer's disease (AD) by activating STAT3 in vitro. They also ameliorate functional memory impairment of mice induced by anticholinergic drugs or soluble toxic amyloid-beta (Abeta) in vivo when either is directly administered into the cerebral ventricle or intraperitoneally injected. However, the mechanism underlying the in vivo effect remains uncharacterized. In addition, from the standpoint of clinical application, drug delivery methods that are less invasive and specific to the central nervous system (CNS) should be developed. In this study, we show that intranasally (i.n.) administered CLN can be successfully transferred to CNS via the olfactory bulb. Using several behavioral tests, we have demonstrated that i.n. administered CLN ameliorates memory impairment of AD models in a dose-responsive manner. Attenuation of AD-related memory impairment by HN derivatives such as CLN appears to be correlated with an increase in STAT3 phosphorylation levels in the septohippocampal region, suggesting that anti-AD activities of HN derivatives may be mediated by activation of STAT3 in vivo as they are in vitro. We further demonstrate that CLN treatment inhibits an Abeta induced decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the medial septum. Combined with the finding that HN derivatives upregulate mRNA expression of neuronal ChAT and vesicular acetylcholine transporter (VAChT) in vitro, it is assumed that CLN may ameliorate memory impairment of AD models by supporting cholinergic neurotransmission, which is at least partly mediated by STAT3-mediated transcriptional upregulation of ChAT and VAChT.
Yamada
Marina
M
Department of Anatomy, KEIO University School of Medicine, Tokyo, Japan.
Chiba
Tomohiro
T
Sasabe
Jumpei
J
Terashita
Kenzo
K
Aiso
Sadakazu
S
Matsuoka
Masaaki
M
D000110:Acetylcholinesterase / Q000097:blood; D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D018680:Cholinergic Antagonists / Q000627:therapeutic use; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology*; D051379:Mice; D008813:Mice, Inbred ICR; D018727:Muscarinic Antagonists / Q000633:toxicity; D009830:Olfactory Bulb / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000502:physiology; D012601:Scopolamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects
D016229:Amyloid beta-Peptides; D018680:Cholinergic Antagonists; C508523:Colivelin; D047908:Intracellular Signaling Peptides and Proteins; D018727:Muscarinic Antagonists; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D012601:Scopolamine; D000110:Acetylcholinesterase