Journal
EXPERT OPINION ON THERAPEUTIC TARGETS
Volume 13, Issue 10, Pages 1155-1167Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1517/14728220903213426
Keywords
Alzheimer's disease (AD); colivelin (CLN); humanin (HN); Janus kinase 2 (JAK2); memory impairment; neuroprotection; signal transducer and activator of transcription 3 (STAT3)
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Funding
- Japan Society for the Promotion of Science (JSPS)
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Background: Amyloid P (A beta) 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/condusions: The JAK2/STAT3 axis is a major transducer of HN-mediated neuroprotective activity. A beta-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.
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