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Inhibition of phosphodiesterase‐4 reverses memory deficits produced by beta‐amyloid peptide in rats
Author(s) -
Cheng YuFang,
Wang Chuang,
Huang Ying,
Xu JiangPing,
Zhang HanTing
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.586.4
Subject(s) - rolipram , hippocampal formation , hippocampus , phosphodiesterase , creb , amyloid beta , chemistry , neuroscience , medicine , endocrinology , memory impairment , pharmacology , psychology , peptide , biochemistry , enzyme , cognition , transcription factor , gene
PDE4, an enzyme that catalyzes hydrolysis of cAMP, is important in mediating memory. However, little is known about its role in memory loss associated with Alzhemer's disease (AD). In the Morris water maze test, microinfusions of beta‐amyloid peptide 25‐35 (Abeta; 10 µg/side) into bilateral CA1 subregions of the hippocampus increased the escape latency during the acquisition trials and decreased the swimming time and distance in the target quadrant in the probe trial test performed 24 h after the last acquisition trial; these were reversed by chronic treatment with rolipram (0.5 mg/kg/d, i.p., 14 d). Consistent with these, in the step‐through passive avoidance test, Abeta infused into CA1 decreased the latency and increased errors entering the dark compartment, which were examined 24 h after initial training; rolipram also reversed the effects of Abeta. Immunoblot analysis revealed a decrease in hippocampal phospho‐CREB induced by Abeta, which was blocked by rolipram. Interestingly, Abeta‐induced memory deficit was reversed by CA1 infusions of lentiviral vectors containing microRNAs that targeted PDE4D4 and PDE4D5, two important PDE4 variants in the hippocampus. Taken together, these results suggest that inhibition of PDE4 reverses memory deficits induced by Abeta; PDE4, in particular its PDE4D4/5 variants, mediates AD‐related memory loss and could be a novel target for treatment of this disorder.