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Phosphodiesterase Inhibition to Target the Synaptic Dysfunction in Alzheimer’s Disease

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Neurodegenerative Diseases

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 6))

Abstract

Alzheimer’s Disease (AD) is a disease of synaptic dysfunction that ultimately proceeds to neuronal death. There is a wealth of evidence that indicates the final common mediator of this neurotoxic process is the formation and actions on synaptotoxic b-amyloid (Aβ). The premise in this review is that synaptic dysfunction may also be an initiating factor in for AD and promote synaptotoxic Aβ formation. This latter hypothesis is consistent with the fact that the most common risk factors for AD, apolipoprotein E (ApoE) allele status, age, education, and fitness, encompass suboptimal synaptic function. Thus, the synaptic dysfunction in AD may be both cause and effect, and remediating synaptic dysfunction in AD may have acute effects on the symptoms present at the initiation of therapy and also slow disease progression. The cyclic nucleotide (cAMP and cGMP) signaling systems are intimately involved in the regulation of synaptic homeostasis. The phosphodiesterases (PDEs) are a superfamily of enzymes that critically regulate spatial and temporal aspects of cyclic nucleotide signaling through metabolic inactivation of cAMP and cGMP. Thus, targeting the PDEs to promote improved synaptic function, or ‘synaptic resilience’, may be an effective and facile approach to new symptomatic and disease modifying therapies for AD. There continues to be a significant drug discovery effort aimed at discovering PDE inhibitors to treat a variety of neuropsychiatric disorders. Here we review the current status of those efforts as they relate to potential new therapies for AD.

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Authors and Affiliations

  1. Neuroscience Biology, Pfizer Global Research & Development, Groton, CT, 06355, USA

    Kelly R. Bales

  2. In Vivo Neuropharmacology, H. Lundbeck A/S, 2500, Valby, Denmark

    Niels Plath

  3. Medicinal Chemistry Research, H. Lundbeck A/S, 2500, Valby, Denmark

    Niels Svenstrup

  4. Mnemosyne Pharmaceuticals, Inc., 3 Davol Sq., Providence, RI, 02903, USA

    Frank S. Menniti

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  1. Kelly R. Bales
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  2. Niels Plath
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  4. Frank S. Menniti
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Correspondence to Frank S. Menniti .

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    Celia Dominguez

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Bales, K.R., Plath, N., Svenstrup, N., Menniti, F.S. (2010). Phosphodiesterase Inhibition to Target the Synaptic Dysfunction in Alzheimer’s Disease. In: Dominguez, C. (eds) Neurodegenerative Diseases. Topics in Medicinal Chemistry, vol 6. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2010_8

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