Tomohiro Chiba1, Marina Yamada, Sadakazu Aiso. 1. Keio University School of Medicine, Department of Anatomy, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. chibat@sc.itc.keio.ac.jp
Abstract
BACKGROUND: Amyloid beta (Abeta) has long been implicated in the pathogenesis of Alzheimer's disease (AD). Little is known, however, about the intracellular events in neurons which lead to memory loss related to AD. Focusing on the fact that an AD-specific neuroprotective peptide named humanin (HN) inhibits AD-related neurotoxicity by activating the JAK2/STAT3 signaling axis, we recently found that age- and disease-dependent deterioration in the JAK2/STAT3 axis plays a critical role in the pathogenesis of AD. OBJECTIVE/ METHODS: Here we summarize the neuroprotective effect of HN and its derivative, named colivelin (CLN), and also review the roles of the JAK2/STAT3 axis in memory impairment related to AD. RESULTS/ CONCLUSIONS: The JAK2/STAT3 axis is a major transducer of HN-mediated neuroprotective activity. Abeta-dependent inactivation of the JAK2/STAT3 axis in hippocampal neurons causes cholinergic dysfunction via pre- and post-synaptic mechanisms, which leads to memory impairment related to AD. This provides not only a novel pathological hallmark of AD but also a novel target in AD therapy.
BACKGROUND:Amyloid beta (Abeta) has long been implicated in the pathogenesis of Alzheimer's disease (AD). Little is known, however, about the intracellular events in neurons which lead to memory loss related to AD. Focusing on the fact that an AD-specific neuroprotective peptide named humanin (HN) inhibits AD-related neurotoxicity by activating the JAK2/STAT3 signaling axis, we recently found that age- and disease-dependent deterioration in the JAK2/STAT3 axis plays a critical role in the pathogenesis of AD. OBJECTIVE/ METHODS: Here we summarize the neuroprotective effect of HN and its derivative, named colivelin (CLN), and also review the roles of the JAK2/STAT3 axis in memory impairment related to AD. RESULTS/ CONCLUSIONS: The JAK2/STAT3 axis is a major transducer of HN-mediated neuroprotective activity. Abeta-dependent inactivation of the JAK2/STAT3 axis in hippocampal neurons causes cholinergic dysfunction via pre- and post-synaptic mechanisms, which leads to memory impairment related to AD. This provides not only a novel pathological hallmark of AD but also a novel target in AD therapy.
Authors: Andrea Vergani; Sara Tezza; Francesca D'Addio; Carmen Fotino; Kaifeng Liu; Monika Niewczas; Roberto Bassi; R Damaris Molano; Sonja Kleffel; Alessandra Petrelli; Antonio Soleti; Enrico Ammirati; Maria Frigerio; Gary Visner; Fabio Grassi; Maria E Ferrero; Domenico Corradi; Reza Abdi; Camillo Ricordi; Mohamed H Sayegh; Antonello Pileggi; Paolo Fiorina Journal: Circulation Date: 2012-12-18 Impact factor: 29.690