Abstract
Between 20% and 25% of patients diagnosed with Alzheimer’s disease (AD) do not have amyloid burden as assessed by positron emission tomography imaging. Thus, there is a need for nonamyloid-directed therapies for AD, especially for those patients with non-amyloid AD. The family of phosphodiesterase-4 (PDE4) enzymes are underexploited therapeutic targets for central nervous system indications. While the PDE4A, B, and D subtypes are expressed in brain, the strict amino acid sequence conservation of the active site across the four subtypes of PDE4 has made it difficult to discover subtype inhibitors. The recent elucidation of the structure of the PDE4 N- and C-terminal regulatory domains now makes it possible to design subtype-selective, negative allosteric modulators (PDE4-NAMs). These act through closing the N-terminal UCR2 or C-terminal CR3 regulatory domains, and thereby inhibit the enzyme by blocking access of cyclic adenosine monophosphate (cAMP) to the active site. PDE4B-NAMs have the potential to reduce neuroinflammation by dampening microglia cytokine production triggered by brain amyloid, while PDE4D-NAMs have potent cognitive benefit by augmenting signaling through the cAMP/protein kinase A/cAMP response element-binding protein (CREB) pathway for memory consolidation. The importance of PDE4D for human cognition is underscored by the recent discovery of PDE4D mutations in acrodysostosis (ACRDY2: MIM 600129), an ultra rare disorder associated with intellectual disability. Thus, the family of PDE4 enzymes provides rich opportunities for the development of mechanistically novel drugs to treat neuroinflammation or the cognitive deficits in AD.
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References
Hurd MD, Martorell P, Delavande A, Mullen KJ, Langa KM. Monetary costs of dementia in the United States. N Engl J Med 2013;368:1326-1334.
Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120:885-890.
Goate A, Chartier-Harlin MC, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991;349:704-706.
Murrell J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 1991;254:97-99.
Mullan M, Crawford F, Axelman K, et al. A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1992;1:345-347.
Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995;375:754-760.
Scheuner D, Eckman C, Jensen M, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 1996;2:864-870.
Jonsson T, Atwal JK, Steinberg S, et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 2012;488:96-99.
Pangalos MN, Jacobsen SJ, Reinhart PH. Disease modifying strategies for the treatment of Alzheimer's disease targeted at modulating levels of the beta-amyloid peptide. Biochem Soc Trans 2005;33:553-558.
Robakis NK, Ramakrishna N, Wolfe G, Wisniewski HM. Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci U S A 1987;84:4190-4194.
Cai XD, Golde TE, Younkin SG. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science 1993;259:514-516.
Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 1999;402:533-537.
Sinha S, Anderson JP, Barbour R, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999;402:537-540.
Vassar R, Bennett BD, Babu-Khan S, et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999;286:735-741.
Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004;55:306-319.
Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:322-333.
Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:311-321.
Li YF, Cheng YF, Huang Y, et al. Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J Neurosci 2011;31:172-183.
Tully T, Bourtchouladze R, Scott R, Tallman J. Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov 2003;2:267-277.
Jin SL, Lan L, Zoudilova M, Conti M. Specific role of phosphodiesterase 4B in lipopolysaccharide-induced signaling in mouse macrophages. J Immunol 2005;175:1523-1531.
Burgin AB, Magnusson OT, Singh J, et al. Design of phosphodiesterase type 4D (PDE4D) allosteric modulators for cognition with improved safety. Nat Biotechnol 2010;28:63-70.
Fox D, 3rd, Burgin AB, Gurney ME. Structural basis for the design of selective phosphodiesterase 4B inhibitors. Cell Signal 2014;26:657-663.
Bolger G, Michaeli T, Martins T, et al. A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs. Mol Cell Biol 1993;13:6558-6571.
Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 2003;370:1-18.
Swinnen JV, Joseph DR, Conti M. Molecular cloning of rat homologues of the Drosophila melanogaster dunce cAMP phosphodiesterase: evidence for a family of genes. Proc Natl Acad Sci U S A 1989;86:5325-5329.
Monaco L, Vicini E, Conti M. Structure of two rat genes coding for closely related rolipramsensitive cAMP phosphodiesterases. Multiple mRNA variants originate from alternative splicing and multiple start sites. J Biol Chem 1994;269:347-357.
Houslay MD, Baillie GS, Maurice DH. cAMP-specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res 2007;100:950-966.
Mori F, Perez-Torres S, De Caro R, et al. The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D. J Chem Neuroanat 2010;40:36-42.
Perez-Torres S, Miro X, Palacios JM, Cortes R, Puigdomenech P, Mengod G. Phosphodiesterase type 4 isozymes expression in human brain examined by in situ hybridization histochemistry and [3H]rolipram binding autoradiography. Comparison with monkey and rat brain. J Chem Neuroanat 2000;20:349-374.
Miro X, Perez-Torres S, Puigdomenech P, Palacios JM, Mengod G. Differential distribution of PDE4D splice variant mRNAs in rat brain suggests association with specific pathways and presynaptical localization. Synapse 2002;45:259-269.
Richter W, Jin SL, Conti M. Splice variants of the cyclic nucleotide phosphodiesterase PDE4D are differentially expressed and regulated in rat tissue. Biochem J 2005;388:803-811.
Cherry JA, Davis RL. Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J Comp Neurol 1999;407:287-301.
Reneerkens OA, Rutten K, Steinbusch HW, Blokland A, Prickaerts J. Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. Psychopharmacology (Berl) 2009;202:419-443.
Imanishi T, Sawa A, Ichimaru Y, et al. Ameliorating effects of rolipram on experimentally induced impairments of learning and memory in rodents. Eur J Pharmacol 1997;321:273-278.
Titus DJ, Sakurai A, Kang Y, et al. Phosphodiesterase inhibition rescues chronic cognitive deficits induced by traumatic brain injury. J Neurosci 2013;33:5216-5226.
DeMarch Z, Giampa C, Patassini S, Bernardi G, Fusco FR. Beneficial effects of rolipram in the R6/2 mouse model of Huntington’s disease. Neurobiol Dis 2008;30:375-387.
Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest 2004;114:1624-1634.
Vitolo OV, Sant’Angelo A, Costanzo V, Battaglia F, Arancio O, Shelanski M. Amyloid beta -peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc Natl Acad Sci U S A 2002;99:13217-13221.
Wang C, Yang XM, Zhuo YY, et al. The phosphodiesterase-4 inhibitor rolipram reverses Abeta-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats. Int J Neuropsychopharmacol 2012;15:749-766.
Cheng YF, Wang C, Lin HB, et al. Inhibition of phosphodiesterase-4 reverses memory deficits produced by Abeta25-35 or Abeta1-40 peptide in rats. Psychopharmacology 2010;212:181-191.
Gong B. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest 2004;114:1624-1634.
Smith DL, Pozueta J, Gong B, Arancio O, Shelanski M. Reversal of long-term dendritic spine alterations in Alzheimer disease models. Proc Natl Acad Sci U S A 2009;106:16877-16882.
Kreisl WC, Lyoo CH, McGwier M, et al. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain 2013;136:2228-2238.
Jin SL, Conti M. Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS activated TNF-alpha responses. Proc Natl Acad Sci U S A 2002;99:7628-7633.
Oliva AA, Jr., Kang Y, Furones C, et al. Phosphodiesterase isoform-specific expression induced by traumatic brain injury. J Neurochem 2012;123:1019-1029.
Ghosh M, Garcia-Castillo D, Aguirre V, et al. Proinflammatory cytokine regulation of cyclic AMP-phosphodiesterase 4 signaling in microglia in vitro and following CNS injury. Glia 2012;60:1839-1859.
Sebastiani G, Morissette C, Lagace C, et al. The cAMPspecific phosphodiesterase 4B mediates Abeta-induced microglial activation. Neurobiol Aging 2006;27:691-701.
Naganuma K, Omura A, Maekawara N, et al. Discovery of selective PDE4B inhibitors. Bioorg Med Chem Lett 2009;19:3174-3176.
Goto T, Shiina A, Yoshino T, et al. Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors. Bioorg Med Chem Lett 2013;23:3325-3328.
Card GL, England BP, Suzuki Y, et al. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure 2004;12:2233-2247.
Dudai Y, Jan YN, Byers D, Quinn WG, Benzer S. dunce, a mutant of Drosophila deficient in learning. Proc Natl Acad Sci U S A 1976;73:1684-1688.
Byers D, Davis RL, Kiger JA, Jr. Defect in cyclic AMP phosphodiesterase due to the dunce mutation of learning in Drosophila melanogaster. Nature 1981;289:79-81.
Chen CN, Denome S, Davis RL. Molecular analysis of cDNA clones and the corresponding genomic coding sequences of the Drosophila dunce + gene, the structural gene for cAMP phosphodiesterase. Proc Natl Acad Sci U S A 1986;83:9313-9317.
Bailey CH, Bartsch D, Kandel ER. Toward a molecular definition of long-term memory storage. Proc Natl Acad Sci U S A 1996;93:13445-13452.
Li YF, Cheng YF, Huang Y, et al. Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J Neurosci 2011;31:172-183.
Bruno O, Fedele E, Prickaerts J, et al. GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses. Br J Pharmacol 2011;164:2054-2063.
Davis RL, Takayasu H, Eberwine M, Myres J. Cloning and characterization of mammalian homologs of the Drosophila dunce + gene. Proc Natl Acad Sci U S A 1989;86:3604-3608.
Sette C, Conti M. Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. Involvement of serine 54 in the enzyme activation. J Biol Chem 1996;271:16526-16534.
Hoffmann R, Wilkinson IR, McCallum JF, Engels P, Houslay MD. cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model. Biochem J 1998;333(Pt 1):139-149.
Richter W, Conti M. Dimerization of the type 4 cAMP-specific phosphodiesterases is mediated by the upstream conserved regions (UCRs). J Biol Chem 2002;277:40212-40221.
Richter W, Conti M. The oligomerization state determines regulatory properties and inhibitor sensitivity of type 4 cAMP-specific phosphodiesterases. J Biol Chem 2004;279:30338-30348.
Lee H, Graham JM, Jr., Rimoin DL, et al. Exome sequencing identifies PDE4D mutations in acrodysostosis. Am J Hum Genet 2012;90:746-751.
Linglart A, Fryssira H, Hiort O, et al. PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance. J Clin Endocrinol Metab 2012;97:E2328-E2338.
Lynch DC, Dyment DA, Huang L, et al. Identification of novel mutations confirms Pde4d as a major gene causing acrodysostosis. Hum Mutat 2013;34:97-102.
Michot C, Le Goff C, Goldenberg A, et al. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am J Hum Genet 2012;90:740-745.
Butler MG, Rames LJ, Wadlington WB. Acrodysostosis: report of a 13-year-old boy with review of literature and metacarpophalangeal pattern profile analysis. Am J Med Genet 1988;30:971-980.
Lee ME, Markowitz J, Lee JO, Lee H. Crystal structure of phosphodiesterase 4D and inhibitor complex(1). FEBS Lett 2002;530:53-58.
Cooper DM. Regulation and organization of adenylyl cyclases and cAMP. Biochem J 2003;375:517-529.
Warrier S, Ramamurthy G, Eckert RL, Nikolaev VO, Lohse MJ, Harvey RD. cAMP microdomains and L-type Ca2+ channel regulation in guinea-pig ventricular myocytes. J Physiol 2007;580:765-776.
Terrin A, Di Benedetto G, Pertegato V, et al. PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. J Cell Biol 2006;175:441-451.
Willoughby D, Wong W, Schaack J, Scott JD, Cooper DM. An anchored PKA and PDE4 complex regulates subplasmalemmal cAMP dynamics. EMBO J 2006;25:2051-2061.
Gervasi N, Tchenio P, Preat T. PKA dynamics in a Drosophila learning center: coincidence detection by rutabaga adenylyl cyclase and spatial regulation by dunce phosphodiesterase. Neuron 2010;65:516-529.
Castro LR, Gervasi N, Guiot E, et al. Type 4 phosphodiesterase plays different integrating roles in different cellular domains in pyramidal cortical neurons. J Neurosci 2010;30:6143-6151.
Wang H, Peng MS, Chen Y, et al. Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors. Biochem J 2007;408:193-201.
Sutcliffe JS, Beaumont V, Watson JM, et al. Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis). PLoS One 2014;9:e102449.
Acknowledgments
This study was funded by the National Institute of Neurological Disorders and Stroke award U01NS078034 and by the National Institute of Mental Health award 5R43MH091791 to M.E.G.
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Gurney, M.E., D’Amato, E.C. & Burgin, A.B. Phosphodiesterase-4 (PDE4) Molecular Pharmacology and Alzheimer’s Disease. Neurotherapeutics 12, 49–56 (2015). https://doi.org/10.1007/s13311-014-0309-7
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DOI: https://doi.org/10.1007/s13311-014-0309-7