Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice.
Misfolded amyloid beta peptide (Abeta) is a pathological hallmark of Alzheimer's disease (AD), a neurodegenerative illness characterized by cognitive deficits and neuronal loss. Transgenic mouse models of Abeta over-production indicate that Abeta-induced cognitive deficits occur in the absence of overt neuronal death, suggesting that while extensive neuronal death may be associated with later stages of the human disease, subtle physiological changes may underlie initial cognitive deficits. Therefore, identifying signaling elements involved in those Abeta-induced cognitive impairments that occur prior to loss of neurons may reveal new potential pharmacological targets. Here, we report that the enzymatic activity of calcineurin, a key protein phosphatase involved in phosphorylation-dependent kinase activity crucial for synaptic plasticity and memory function, is upregulated in the CNS of the Tg2576 animal model for Abeta over-production. Furthermore, acute treatment of Tg2576 mice with the calcineurin inhibitor FK506 (10mg/kg i.p.) improves memory function. These results indicate that calcineurin may mediate some of the cognitive effects of excess Abeta such that inhibition of calcineurin shall be further explored as a potential treatment to reverse cognitive impairments in AD.
Dineley
Kelly T
KT
Department of Neurology, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1043, USA.
Hogan
Dale
D
Zhang
Wen-Ru
WR
Taglialatela
Giulio
G
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001245:Association Learning / Q000187:drug effects*; D065095:Calcineurin Inhibitors; D016923:Cell Death; D003071:Cognition / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016559:Tacrolimus / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016559:Tacrolimus