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

Elevation of intracranial soluble amyloid-beta (A beta) 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 Ab 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 A beta 1-42 downregulated p-STAT3 whereas passive immunization with anti-A beta antibody conversely restored hippocampal p-STAT3 levels in Tg2576 mice, paralleling the decrease in the brain Ab burden. A beta 1-42 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: A beta-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.