Gene silencing of phosphodiesterase-4D (PDE4D) as a therapeutic approach to beta

Summary

Principal Investigator: Han Ting Zhang
Abstract: DESCRIPTION (provided by applicant): Phosphodiesterase-4 (PDE4), an enzyme catalyzing the breakdown of cyclic AMP (cAMP), has been implicated in memory impairment associated with Alzheimer's disease (AD). Inhibition of PDE4 increases intracellular cAMP and subsequently activates its downstream target cAMP-responsive-element-binding protein (CREB). Primarily through this mechanism, the PDE4 inhibitor rolipram not only counteracts the inhibitory effects of high levels of amyloid-beta peptide (Abeta) on cAMP signaling and memory, but also delays the natural progression of Abeta-induced synaptic and cognitive abnormalities. These point to PDE4 as a potential target for the treatment of memory deficits in AD. Based on recent data from our laboratory and others, we hypothesize that, among the four PDE4 subtypes (PDE4-A, B, C, and D), PDE4D plays a major role in the mediation of memory loss associated with AD. Thus, inhibition or knockdown of PDE4D should result in reversal of Abeta-induced cAMP/CREB inhibition and memory deficits. The primary objective of this proposal is to test this hypothesis in a rodent model. For this purpose, the following specific aims are proposed. First, determine whether knockdown of PDE4D reverses Abeta-induced inhibition of cAMP/CREB signaling in vitro. This will be accomplished by detecting levels of cAMP and phospho-CREB (pCREB) in primary cultures of hippocampal neurons treated with Abeta1-42 (Abeta42) and lentiviral vectors expressing microRNAs (miRNAs) of PDE4D4 and PDE4D5, the primary PDE4D variants in the hippocampus. Second, determine whether PDE4D knockdown in the hippocampus reverses Abeta- induced deficits of cAMP signaling and memory. This will be accomplished by examining pCREB levels in the hippocampus in vivo and memory performance using the Morris water-maze task in rats, which are administered Abeta42 following the knockdown of PDE4D by miRNAs. Gene silencing will be carried out by microinfusions of lenti-PDE4D4/5-miRNAs into bilateral CA1 subregions of the rat hippocampus. Successful completion of these experiments will lead to a better understanding of the role of PDE4D in cAMP signaling and the determination of the contribution of PDE4D to memory deficits associated with AD. Using miRNA gene silencing, a powerful and unique technique for identifying gene functions, will make this happen and aid and encourage the development of PDE4 subtype-selective inhibitors as novel treatments for AD, which affects nearly 5 million Americans. This is an issue of high relevance to public health. Since knockdown of a specific PDE4 subtype has never been investigated in neurons, this project involves considerable risk such as the possible ineffectiveness of PDE4D-miRNAs. Nevertheless, it may lead to an extensive exploration of functions of PDE4 subtypes and even their 22 splice variants by the innovative use of gene silencing. The outcomes of this project could lead to a breakthrough in the PDE research area and have major impact on research of PDE4, a potential target for treatment of neurodegenerative disorders such as AD. PUBLIC HEALTH RELEVANCE: It has been found that an enzyme called phosphodiesterase-4 (PDE4), which helps in the breakdown of the important intracellular second messenger cyclic AMP (cAMP), plays an important role in mediating memory regulation in Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive loss of memory and commonly found in people over age 65. We propose experiments to find out whether reducing activity of one form, PDE4D, in the rat hippocampus reverses memory deficits and cAMP signaling decreases induced by misfolded proteins called beta amyloid (Abeta), which critically contributes to memory loss in AD. If these experiments are successful, they will not only help understand the important contribution of PDE4D to cAMP signaling and memory associated with AD, but encourage and accelerate the development of selective blockers of PDE4D for treating memory loss in AD, which affects approximately 20 million people worldwide and nearly 5 million people in the United States.
Funding Period: 2008-08-01 - 2010-07-31
more information: NIH RePORT

Top Publications

  1. ncbi RNA interference-mediated knockdown of long-form phosphodiesterase-4D (PDE4D) enzyme reverses amyloid-β42-induced memory deficits in mice
    Cong Zhang
    Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China Departments of Behavioral Medicine and Psychiatry and Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV, USA
    J Alzheimers Dis 38:269-80. 2014
  2. pmc PDE4 as a target for cognition enhancement
    Wito Richter
    University of California San Francisco, Department of Obstetrics, Gynecology and Reproductive Sciences, San Francisco, CA 94143 0556, USA
    Expert Opin Ther Targets 17:1011-27. 2013
  3. pmc Senescent-induced dysregulation of cAMP/CREB signaling and correlations with cognitive decline
    Rolf T Hansen
    Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA
    Brain Res 1516:93-109. 2013
  4. pmc RNA interference-mediated phosphodiesterase 4D splice variants knock-down in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects
    Zhen Zhen Wang
    Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China
    Br J Pharmacol 168:1001-14. 2013
  5. ncbi The phosphodiesterase-4 inhibitor rolipram reverses Aβ-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats
    Chuang Wang
    Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
    Int J Neuropsychopharmacol 15:749-66. 2012
  6. ncbi Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats
    Ling Xia Li
    Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, People s Republic of China
    Metab Brain Dis 26:37-47. 2011
  7. pmc Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling
    Yun Feng Li
    Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, West Virginia 26506, USA
    J Neurosci 31:172-83. 2011
  8. ncbi Inhibition of phosphodiesterase-4 reverses memory deficits produced by Aβ25-35 or Aβ1-40 peptide in rats
    Yu Fang Cheng
    Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People s Republic of China
    Psychopharmacology (Berl) 212:181-91. 2010
  9. pmc Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus
    Yun Feng Li
    Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV 26506 9137, USA
    Neuropsychopharmacology 34:2404-19. 2009
  10. ncbi Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs
    Han Ting Zhang
    Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV 26506 9137, USA
    Curr Pharm Des 15:1688-98. 2009

Scientific Experts

  • Han Ting Zhang
  • Yun Feng Li
  • Chuang Wang
  • Yu Fang Cheng
  • Steven P Wilson
  • JAMES M O'DONNELL
  • Huan Bing Lin
  • Jiang Ping Xu
  • Ying Huang
  • Cong Zhang
  • Zhen Zhen Wang
  • Rolf T Hansen
  • Wito Richter
  • Marco Conti
  • Ling Xia Li
  • Yufang Cheng
  • Haitao Wang
  • Jiangping Xu
  • Li Yuan
  • You Zhi Zhang
  • Lei An
  • Xiao Yun Wang
  • Yan Qin Liu
  • Jing Li
  • Yi Zhang
  • Nan Zhao
  • Frank S Menniti
  • Juan Juan Qin
  • Xue Mei Yang
  • Ye Ye Zhuo
  • Heng Zhou
  • Lan Xiao
  • Simon L Amsdell

Detail Information

Publications10

  1. ncbi RNA interference-mediated knockdown of long-form phosphodiesterase-4D (PDE4D) enzyme reverses amyloid-β42-induced memory deficits in mice
    Cong Zhang
    Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China Departments of Behavioral Medicine and Psychiatry and Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV, USA
    J Alzheimers Dis 38:269-80. 2014
    ..01), and NF-κB (p65) (p < 0.05) in the hippocampus of Aβ42-challenged mice. These results suggest that long-form PDE4D knockdown may offer a promising treatment for memory loss associated with Alzheimer's disease. ..
  2. pmc PDE4 as a target for cognition enhancement
    Wito Richter
    University of California San Francisco, Department of Obstetrics, Gynecology and Reproductive Sciences, San Francisco, CA 94143 0556, USA
    Expert Opin Ther Targets 17:1011-27. 2013
    ..Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs...
  3. pmc Senescent-induced dysregulation of cAMP/CREB signaling and correlations with cognitive decline
    Rolf T Hansen
    Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA
    Brain Res 1516:93-109. 2013
    ..Overall, understanding the senescent-related changes that occur in cAMP/CREB signaling could be important for the development of novel drug targets for both healthy aging, and pathological aging such as Alzheimer's disease...
  4. pmc RNA interference-mediated phosphodiesterase 4D splice variants knock-down in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects
    Zhen Zhen Wang
    Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China
    Br J Pharmacol 168:1001-14. 2013
    ..Therefore, the aim of present research was to investigate whether long-form PDE4D variants mediate antidepressant-like and cognition-enhancing effects, but are irrespective with emesis...
  5. ncbi The phosphodiesterase-4 inhibitor rolipram reverses Aβ-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats
    Chuang Wang
    Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
    Int J Neuropsychopharmacol 15:749-66. 2012
    ..PDE4 could be a target for treatment of memory loss associated with AD...
  6. ncbi Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats
    Ling Xia Li
    Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, People s Republic of China
    Metab Brain Dis 26:37-47. 2011
    ..PDE4 may be a target for treatment of cognitive disorders associated with cerebral ischemia...
  7. pmc Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling
    Yun Feng Li
    Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, West Virginia 26506, USA
    J Neurosci 31:172-83. 2011
    ..These novel findings will aid in the development of PDE4 subtype- or variant-selective inhibitors for treatment of disorders involving impaired cognition, including Alzheimer's disease...
  8. ncbi Inhibition of phosphodiesterase-4 reverses memory deficits produced by Aβ25-35 or Aβ1-40 peptide in rats
    Yu Fang Cheng
    Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, People s Republic of China
    Psychopharmacology (Berl) 212:181-91. 2010
    ..However, little is known about whether inhibition of phosphodiesterase-4 (PDE4), which increases intracellular cAMP, reverses β-amyloid peptide (Aβ)-induced memory deficits...
  9. pmc Antidepressant- and anxiolytic-like effects of the phosphodiesterase-4 inhibitor rolipram on behavior depend on cyclic AMP response element binding protein-mediated neurogenesis in the hippocampus
    Yun Feng Li
    Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV 26506 9137, USA
    Neuropsychopharmacology 34:2404-19. 2009
    ....
  10. ncbi Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs
    Han Ting Zhang
    Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV 26506 9137, USA
    Curr Pharm Des 15:1688-98. 2009
    ..This review also discusses the relationship between PDE4 and antidepressant activity based on structures, brain distributions, and pharmacological properties of PDE4 and its isoforms...