Alzheimer's disease (AD) is the most common cause of
dementia.
Humanin (HN) is a short bioactive
peptide abolishing neuronal cell death induced by various familial AD (
FAD)-causative genes and
amyloid-beta (Abeta) in vitro. It has been shown that HN suppresses memory impairment of mice induced by intracerebroventricular administration of Abeta. To potentiate the
neuroprotective effect of HN, we synthesized a hybrid
peptide named
Colivelin composed of
activity-dependent neurotrophic factor (ADNF) C-terminally fused to
AGA-(C8R)HNG17, a potent HN derivative.
Colivelin completely suppresses death induced by overexpressed
FAD-causative genes and Abeta1-43 at a concentration of 100 fM, whereas
AGA-(C8R)HNG17 does so at a concentration of 10 pM.
Colivelin-induced neuroprotection has been confirmed to occur via two neuroprotective pathways: one mediated by Ca2+/
calmodulin-dependent protein kinase IV, triggered by ADNF, and one mediated by
signal transducer and activator of transcription 3, triggered by HN. In vivo animal studies have further indicated that intracerebroventricular administration of
Colivelin not only completely suppresses impairment in spatial working memory induced by repetitive intracerebroventricular injection of
Abeta25-35 or Abeta1-42, but also it antagonizes neuronal loss in the CA1 region of hippocampus induced by hippocampal injection of Abeta1-42. In addition, intraperitoneally administered
Colivelin suppresses memory impairment caused by a
muscarinic acetylcholine receptor antagonist, 3-quinuclidinyl benzilate, indicating that a substantial portion of intraperitoneally administered
Colivelin passes through the blood-brain barrier and suppresses functional
memory deficit. Thus,
Colivelin might serve as a novel
drug candidate for treatment of AD.