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

T. Chiba, M. Yamada, J. Sasabe, K. Terashita, M. Shimoda, M. Matsuoka, S. Aiso

Research output: Contribution to journalArticle

127 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)206-222
Number of pages17
JournalMolecular Psychiatry
Volume14
Issue number2
DOIs
Publication statusPublished - 2009 Feb 1
Externally publishedYes

Keywords

  • Acetylcholine
  • Alzheimer's disease
  • Hippocampal neurons
  • Memory impairment
  • STAT3

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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