RGD Reference Report - Amyloid-beta causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

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

Authors: Chiba, T  Yamada, M  Sasabe, J  Terashita, K  Shimoda, M  Matsuoka, M  Aiso, S 
Citation: Chiba T, etal., Mol Psychiatry. 2009 Feb;14(2):206-22. doi: 10.1038/mp.2008.105. Epub 2008 Sep 23.
RGD ID: 10403051
Pubmed: PMID:18813209   (View Abstract at PubMed)
DOI: DOI:10.1038/mp.2008.105   (Journal Full-text)

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 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease treatmentISOJak2 (Mus musculus)10403051; 10403051 RGD 
Alzheimer's disease treatmentIMP 10403051 RGD 
Alzheimer's disease  ISOStat3 (Mus musculus)10403051; 10403051protein:decreased tyrosine phosphorylation:dentate gyrus and CA1 field of hippocampus RGD 
Alzheimer's disease  IDA 10403051protein:decreased tyrosine phosphorylation:dentate gyrusRGD 
Alzheimer's disease  ISOSTAT3 (Homo sapiens)10403051; 10403051protein:decreased tyrosine phosphorylation:dentate gyrusRGD 
Alzheimer's disease  IDA 10403051protein:decreased tyrosine phosphorylation:dentate gyrus and CA1 field of hippocampus RGD 

Objects Annotated

Genes (Rattus norvegicus)
Jak2  (Janus kinase 2)
Stat3  (signal transducer and activator of transcription 3)

Genes (Mus musculus)
Jak2  (Janus kinase 2)
Stat3  (signal transducer and activator of transcription 3)

Genes (Homo sapiens)
JAK2  (Janus kinase 2)
STAT3  (signal transducer and activator of transcription 3)


Additional Information