Phosphodiesterases as therapeutic targets for Alzheimer's disease

ACS Chem Neurosci. 2012 Nov 21;3(11):832-44. doi: 10.1021/cn3000907. Epub 2012 Oct 1.


Alzheimer's disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti-beta amyloid pathology has led researchers to focus on other non-amyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDE5 inhibitors have also been shown to effectively restore memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Animals
  • CREB-Binding Protein / metabolism
  • Carrier Proteins / metabolism
  • Cognition / drug effects
  • Disease Models, Animal
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Memory / drug effects
  • Memory Disorders / drug therapy*
  • Mice
  • Nootropic Agents / pharmacology
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / drug effects*
  • Phosphoric Diester Hydrolases / metabolism
  • tau Proteins / drug effects*
  • tau Proteins / metabolism


  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nootropic Agents
  • Phosphodiesterase 4 Inhibitors
  • cyclic GMP-binding protein
  • tau Proteins
  • CREB-Binding Protein
  • Phosphoric Diester Hydrolases