Aβ 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). We here report that phospho(p-) STAT3 levels in hippocampal neurons age-dependently decreased in AD patients. Hippocampal STAT3 activation by colivelin (CLN) treatment completely restored cognitive function in an AD model (Tg2576). Intracerebroventricular (i.c.v.) administration of A beta 1-42 downregulated p-STAT3 while passive immunization with anti-A beta antibody conversely restored hippocampal p-STAT3 levels in Tg2576. Pharmacological inhibition of STAT3 not only downregulated choline acetyltransferase (ChAT) but also desensitized M1-type muscarinic acetylcholine receptor. Thus, we propose a novel hypothesis accounting for memory impairment related to AD: A beta-dependent inactivation of STAT3 causes memory loss through cholinergic dysfunction.