title: Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice.
abstract: Soluble oligomeric aggregates of the amyloid-beta (A beta) peptide are believed to be the most neurotoxic A beta species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that A beta oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of A beta-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric A beta treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of A beta oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by A beta oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice.
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, Texas 77555-1043, USA.
authors.forename: Kelly T
authors.initials: KT
authors.lastname: Dineley
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
authors.forename: Volker
authors.initials: V
authors.lastname: Neugebauer
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.forename: Wenru
authors.initials: W
authors.lastname: Zhang
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Reese
authors.forename: Giulio
authors.initials: G
authors.lastname: Taglialatela
mesh_terms: D058227:Amyloidogenic Proteins / Q000633:toxicity*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D050882:CREB-Binding Protein / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism*; D003213:Conditioning, Psychological / Q000187:drug effects*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005239:Fear / Q000523:psychology*; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007270:Injections, Intra-Articular / Q000379:methods; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques / Q000379:methods; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D058227:Amyloidogenic Proteins; D007166:Immunosuppressive Agents; D050882:CREB-Binding Protein; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases; D020123:Sirolimus; D016559:Tacrolimus