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Amyloid-β causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons

Chiba, T, Yamada, M, Sasabe, J, Terashita, K, Shimoda, M, Matsuoka, M, Aiso, S·2009·Molecular Psychiatry
DOI 10.1038/mp.2008.105
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Abstract

Elevation of intracranial soluble amyloid-beta (Abeta) levels has been implicated in the pathogenesis of Alzheimer's disease (AD). Intracellular events in neurons, which lead to memory loss in AD, however, remain elusive. Humanin (HN) is a short neuroprotective peptide abolishing Abeta neurotoxicity. Recently, we found that HN derivatives activate the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis. We here report that an HN derivative named colivelin completely restored cognitive function in an AD model (Tg2576) by activating the JAK2/STAT3 axis. In accordance, immunofluorescence staining using a specific antibody against phospho- (p-) STAT3 revealed that p-STAT3 levels in hippocampal neurons age-dependently decreased in both AD model mice and AD patients. Intracerebroventricular administration of Abeta1-42 downregulated p-STAT3 whereas passive immunization with anti-Abeta antibody conversely restored hippocampal p-STAT3 levels in Tg2576 mice, paralleling the decrease in the brain Abeta burden. Abeta1-42 consistently modulated p-STAT3 levels in primary neurons. Pharmacological inhibition of the JAK2/STAT3 axis not only induced significant loss of spatial working memory by downregulating an acetylcholine-producing enzyme choline acetyltransferase but also desensitized the M(1)-type muscarinic acetylcholine receptor. Thus, we propose a novel theory accounting for memory impairment related to AD: Abeta-dependent inactivation of th…

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Metadata

Authors
Chiba, T., Yamada, M., Sasabe, J., Terashita, K., Shimoda, M., Matsuoka, M., & Aiso, S.
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2008-09-23
Volume
14
Issue
2
Pages
206-222
ISSN
  • 1359-4184
  • 1476-5578
DOI
10.1038/mp.2008.105
Cited by
194
References
14
Language
en
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