Abstract
Elevation of intracranial soluble amyloid-β (Aβ) 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 Aβ 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 Aβ1–42 downregulated p-STAT3 whereas passive immunization with anti-Aβ antibody conversely restored hippocampal p-STAT3 levels in Tg2576 mice, paralleling the decrease in the brain Aβ burden. Aβ1–42 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 M1-type muscarinic acetylcholine receptor. Thus, we propose a novel theory accounting for memory impairment related to AD: Aβ-dependent inactivation of the JAK2/STAT3 axis causes memory loss through cholinergic dysfunction. Our findings provide not only a novel pathological hallmark in AD but also a novel target in AD therapy.
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Acknowledgements
We are grateful to Dr Ikuo Nishimoto, who initiated the work and unfortunately passed away on 17 October 2003. We are indebted to Dr Yasunori Okada (KEIO University, Japan), Dr Makoto Takagi (Saiseikai Central Hospital, Japan) and Dr Masaki Takao (KEIO University, Japan) for essential help. We also thank Dr Takeshi Tabira (National Institute for Longevity Sciences, Japan) for providing L286V-PS1 Tg mice; Dr Akihiko Yoshimura (Kyushu University, Japan) for providing adenovirus encoding DN-STAT3; Dr Dovie Wylie for expert linguistic assistance; Ms T Hiraki, H Matsumoto and T Yoshida-Nishimoto for indispensable support; Ms S Uchida and Mr S Hayashi for animal husbandry. This work was supported in part by grants from the Japan Society for the Promotion of Science (JSPS), the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), the KEIO Gijuku Academic Development Funds (TC), and NOEVIR CO., LTD. MY is a JSPS research fellow.
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Chiba, T., Yamada, M., Sasabe, J. et al. Amyloid-β causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons. Mol Psychiatry 14, 206–222 (2009). https://doi.org/10.1038/mp.2008.105
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DOI: https://doi.org/10.1038/mp.2008.105
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