RATIONALE: Cyclic AMP signaling plays an important role in memory loss associated with Alzheimer's disease (AD). However, little is known about whether inhibition of phosphodiesterase-4 (PDE4), which increases intracellular cAMP, reverses β-amyloid peptide (Aβ)-induced memory deficits. OBJECTIVE: Experiments were performed to demonstrate the effect of the PDE4 inhibitor rolipram on memory impairment produced by Aβ1-40 (Aβ40) or its core fragment Aβ25-35. METHODS: We tested memory using Morris water-maze and passive avoidance tasks and examined expression of phosphorylated cAMP response-element binding protein (pCREB) in the hippocampus in rats treated with Aβ25-35 or Aβ40 into bilateral CA1 subregions, with or without rolipram administration. RESULTS: Aβ25-35 (10 μg/side) increased escape latency during acquisition training and decreased swimming time and distance in the target quadrant in the water-maze probe trial; it also decreased 24-h retention in the passive avoidance paradigm. All these were reversed by chronic administration of rolipram (0.5 mg/kg). Similarly, Aβ40 (4 μg/side) produced memory impairment, as demonstrated by decreased retention in passive avoidance; this was also reversed by repeated treatment with rolipram. In addition, rolipram blocked extinction of memory during the 32-day testing period in the passive avoidance test. Further, Aβ40 decreased pCREB expression in the hippocampus, which was also reversed by rolipram; the changes in pCREB were highly correlated with those in memory. CONCLUSIONS: These results suggest that the PDE4 inhibitor rolipram reverses cognitive deficits associated with AD most likely via increased cAMP/CREB signaling in the hippocampus; PDE4 could be a target for drugs that improve cognition in AD.
RATIONALE: Cyclic AMP signaling plays an important role in memory loss associated with Alzheimer's disease (AD). However, little is known about whether inhibition of phosphodiesterase-4 (PDE4), which increases intracellular cAMP, reverses β-amyloid peptide (Aβ)-induced memory deficits. OBJECTIVE: Experiments were performed to demonstrate the effect of the PDE4 inhibitor rolipram on memory impairment produced by Aβ1-40 (Aβ40) or its core fragment Aβ25-35. METHODS: We tested memory using Morris water-maze and passive avoidance tasks and examined expression of phosphorylated cAMP response-element binding protein (pCREB) in the hippocampus in rats treated with Aβ25-35 or Aβ40 into bilateral CA1 subregions, with or without rolipram administration. RESULTS: Aβ25-35 (10 μg/side) increased escape latency during acquisition training and decreased swimming time and distance in the target quadrant in the water-maze probe trial; it also decreased 24-h retention in the passive avoidance paradigm. All these were reversed by chronic administration of rolipram (0.5 mg/kg). Similarly, Aβ40 (4 μg/side) produced memory impairment, as demonstrated by decreased retention in passive avoidance; this was also reversed by repeated treatment with rolipram. In addition, rolipram blocked extinction of memory during the 32-day testing period in the passive avoidance test. Further, Aβ40 decreased pCREB expression in the hippocampus, which was also reversed by rolipram; the changes in pCREB were highly correlated with those in memory. CONCLUSIONS: These results suggest that the PDE4 inhibitor rolipram reverses cognitive deficits associated with AD most likely via increased cAMP/CREB signaling in the hippocampus; PDE4 could be a target for drugs that improve cognition in AD.
Authors: M P Lambert; A K Barlow; B A Chromy; C Edwards; R Freed; M Liosatos; T E Morgan; I Rozovsky; B Trommer; K L Viola; P Wals; C Zhang; C E Finch; G A Krafft; W L Klein Journal: Proc Natl Acad Sci U S A Date: 1998-05-26 Impact factor: 11.205
Authors: Han-Ting Zhang; Ying Huang; Neesha U Suvarna; Chengjun Deng; Alicia M Crissman; Allen T Hopper; Michael De Vivo; Gregory M Rose; James M O'Donnell Journal: Psychopharmacology (Berl) Date: 2005-01-26 Impact factor: 4.530
Authors: Donald H Maurice; Hengming Ke; Faiyaz Ahmad; Yousheng Wang; Jay Chung; Vincent C Manganiello Journal: Nat Rev Drug Discov Date: 2014-04 Impact factor: 84.694
Authors: O Bruno; E Fedele; J Prickaerts; L A Parker; E Canepa; C Brullo; A Cavallero; E Gardella; A Balbi; C Domenicotti; E Bollen; H J M Gijselaers; T Vanmierlo; K Erb; C L Limebeer; F Argellati; U M Marinari; M A Pronzato; R Ricciarelli Journal: Br J Pharmacol Date: 2011-12 Impact factor: 8.739
Authors: Ju-Hyun Lee; Devin M Wolfe; Sandipkumar Darji; Mary Kate McBrayer; Daniel J Colacurcio; Asok Kumar; Philip Stavrides; Panaiyur S Mohan; Ralph A Nixon Journal: J Mol Biol Date: 2020-02-24 Impact factor: 5.469