Phosphodiesterase-4 modulation as a potential therapeutic for cognitive loss in pathological and non-pathological aging: Possibilities and pitfalls

Current Pharmaceutical Design

Volumn 21, Issue 3, 2015, Pages 291-302

  Hansen, Rolf T ^a   Zhang, Han Ting ^a  

^a WEST VIRGINIA UNIVERSITY   (United States)

Author keywords

Aging; Alzheimer s disease; CAMP; Cognition; Drug development; PDE4; Pitfall

Indexed keywords

CYCLIC AMP; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; PHOSPHODIESTERASE IV INHIBITOR; PHOSPHODIESTERASE IV;

ALTERNATIVE RNA SPLICING; ARTICLE; COGNITIVE DEFECT; COGNITIVE THERAPY; HUMAN; NEUROMODULATION; NONHUMAN; PRIORITY JOURNAL; SENESCENCE; SIGNAL TRANSDUCTION; AGING; ANIMAL; CHEMISTRY; COGNITION DISORDERS; DRUG EFFECTS; ENZYMOLOGY; PATHOLOGY;

AGING; ANIMALS; COGNITION DISORDERS; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 4; HUMANS; PHOSPHODIESTERASE 4 INHIBITORS;

EID: 84925849849     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/1381612820666140826114208     Document Type: Article

References (187)

1. Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 2003; 370: 1-18.
2. Conti M, Richter W, Mehats C, Livera G, Park J-Y, Jin C. Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem 2003; 278: 5493-6.
3. Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology. Elsevier Ltd 2010; 59: 367-74.
4. Menniti FS, Faraci WS, Schmidt CJ. Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 2006; 5: 660-70.
5. Omori K, Kotera J. Overview of PDEs and their regulation. Circ Res 2007; 100: 309-27.
6. Zhang H-T. Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Curr Pharm Des 2009; 15: 1688-98.
7. 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; 301: 287-301.
8. Johansson EM, Reyes-Irisarri E, Mengod G. Comparison of cAMP-specific phosphodiesterase mRNAs distribution in mouse and rat brain. Neurosci Lett. Elsevier Ireland Ltd 2012; 525: 1-6.
9. McPhee I, Cochran S, Houslay MD. The novel long PDE4A10 cyclic AMP phosphodiesterase shows a pattern of expression within brain that is distinct from the long PDE4A5 and short PDE4A1 isoforms. Cell Signal 2001; 13: 911-8.
10. Jang D-J, Park S-W, Lee J-A, et al. N termini of apPDE4 isoforms are responsible for targeting the isoforms to different cellular membranes. Learn Mem 2010; 17: 469-79.
11. Houslay MD. Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci. Elsevier Ltd 2010; 35: 91-100.
12. Saldou N, Obernolte R, Huber A, et al. Comparison of recombinant human PDE4 isoforms: interaction with substrate and inhibitors. Cell Signal 1998; 10: 427-40.
13. Reeves ML, Leigh BK, England PJ. The identification of a new cyclic nucleotide phosphodiesterase activity in human and guineapig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors. Biochem J 1987; 241: 535-41.
14. Kauvar LM. DEFECTIVE CYCLIC ADENOSINE 3’:5-MONOPHOSPHATE PHOSPHODIESTERASE IN THE DROSOPHILA MEMORY MUTANT DUNCE. J Neurosci 1982; 2: 1347-58.
15. Qui Y, Chen C, Malone T, Richter L, Beckendorf S, Davis R. Characterization of the memory gene dunce of Drosophila melanogaster. J Mol Biol 1991; 222: 553-65.
16. Swinnen J V, 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 USA 1989; 86: 5325-9.
17. 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: 6558-71.
18. O’Donnell JM, Zhang H-T. Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4). Trends Pharmacol Sci 2004; 25: 158-63.
19. Wang P, Myers JG, Wu P, Cheewatrakoolpong B, Egan RW, Billah MM. Expression, Purification, and Characterization of Human Subtypes A, B, C, and D. Biochem Biophys Res Commun 1997; 234: 320-4.
20. 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 [ 3 H ] rolipram binding autoradiography Comparison with monkey and rat brain. J Chem Neuroanat 2000; 20: 349-74.
21. Rena G, Begg F, Ross A, et al. Molecular cloning, genomic positioning, promoter identification, and characterization of the novel cyclic amp-specific phosphodiesterase PDE4A10. Mol Pharmacol 2001 May; 59: 996-1011.
22. Bolger GB, Peden AH, Steele MR, et al. Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2. J Biol Chem 2003; 278: 33351-63.
23. Huston E, Lumb S, Russell A, et al. Molecular cloning and transient expression in COS7 cells of a novel human PDE4B cAMP-specific phosphodiesterase, HSPDE4B3. Biochem J 1997; 328 (Pt 2: 549-58).
24. Shepherd M, McSorley T, Olsen AE, et al. Molecular cloning and subcellular distribution of the novel PDE4B4 cAMP-specific phosphodiesterase isoform. Biochem J 2003; 370: 429-38.
25. Bolger GB, Erdogan S, Jones RE, et al. Characterization of five different mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene. Biochem J 1997; 328: 539-48.
26. Bolger GB, Mcphee I, Houslay MD. Alternative Splicing of cAMP-specific Phosphodiesterase mRNA Transcripts, Characterization of a A Novel Tissue-specific Isoform,. J Biol Chem 1996; 271: 1065-71.
27. Miró X, Pérez-Torres S, Puigdomènech 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: 259-69.
28. Richter W, Jin S-LC, Conti M. Splice variants of the cyclic nucleotide phosphodiesterase PDE4D are differentially expressed and regulated in rat tissue. Biochem J 2005; 388: 803-11.
29. Chandrasekaran A, Toh KY, Low SH, Tay SKH, Brenner S, Goh DLM. Identification and characterization of novel mouse PDE4D isoforms: molecular cloning, subcellular distribution and detection of isoform-specific intracellular localization signals. Cell Signal 2008; 20: 139-53.
30. Wallace DA, Johnston LA, Huston E, et al. Identification and Characterization of PDE4A11, a Novel, Widely Expressed Long Isoform Encoded by the Human PDE4A cAMP Phosphodiesterase Gene. Mol Pharmacol 2005; 67: 1920-34.
31. Mackenzie KF, Topping EC, Bugaj-Gaweda B, et al. Human PDE4A8, a novel brain-expressed PDE4 cAMP-specific phosphodiesterase that has undergone rapid evolutionary change. Biochem J 2008; 411: 361-9.
32. Sullivan M, Rena G, Begg F, Gordon L, Olsen AS, Houslay MD. Identification and characterization of the human homologue of the short PDE4A cAMP-specific phosphodiesterase RD1 (PDE4A1) by analysis of the human HSPDE4A gene locus located at chromosome 19p13.2. Biochem J 1998; 333: 693-703.
33. Richter W, Menniti F, Zhang H, Conti M. PDE4 as a target for cognition enhancement. Expert Opin Ther Targets 2013; 17: 1011-27.
34. Johnson KR, Nicodemus-Johnson J, Danziger RS. An evolutionary analysis of cAMP-specific Phosphodiesterase 4 alternative splicing. BMC Evol Biol 2010; 10: 247.
35. Huston E, Beard M, McCallum F, et al. The cAMP-specific phosphodiesterase PDE4A5 is cleaved downstream of its SH3 interaction domain by caspase-3. Consequences for altered intracellular distribution. J Biol Chem 2000; 275: 28063-74.
36. Millar JK, Pickard BS, Mackie S, et al. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 2005; 310: 1187-91.
37. Porteous DJ, Millar JK, Brandon NJ, Sawa A. DISC1 at 10: connecting psychiatric genetics and neuroscience. Trends Mol Med. Elsevier Ltd 2011; 17: 699-706.
38. Dodge-Kafka KL, Soughayer J, Pare GC, et al. The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 2005; 437: 574-8.
39. Li Y-F, Cheng Y-F, 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: 172-83.
40. Rutten K, Misner DL, Works M, et al. Enhanced long-term potentiation and impaired learning in phosphodiesterase 4Dknockout (PDE4D) mice. Eur J Neurosci 2008; 28: 625-32.
41. Zhang H-T, Huang Y, Jin S-L, et al. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 2002; 27: 587-95.
42. Burgin AB, Magnusson OT, Singh J, et al. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol. Nature Publishing Group 2010; 28: 63-70.
43. 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: 2054-63.
44. Wang Z, Zhang Y, Liu Y, et al. RNA interference-mediated phosphodiesterase 4D splice variants knock-down in the prefrontal cortex produces antidepressant-like and cognition-enhancing effects. Title. Br J Pharmacol 2013; 168: 1004-14.
45. Zhang H-T, Huang Y, Masood A, et al. Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacology 2008; 33: 1611-23.
46. Carlezon W, Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci 2005; 28: 436-45.
47. Dash P, Hochner B, Kandel E. Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks longterm facilitation. Nature 1990; 345: :718-21.
48. Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva A. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 1994; 79: 59-68.
49. Impey S, Mark M, Villacres E, Poser S, Chavkin C, Storm D. Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron 1996; 16: 973-82.
50. Sample V, DiPilato LM, Yang JH, Ni Q, Saucerman JJ, Zhang J. Regulation of nuclear PKA revealed by spatiotemporal manipulation of cAMP. Nat Chem Biol 2012; 8: 375-82.
51. De Rooij J, Zwartkruis FJ, Verheijen MH, et al. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 1998; 396: 474-7.
52. Bos JL. Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci 2006; 31: 680-6.
53. Gloerich M, Bos JL. Epac: defining a new mechanism for cAMP action. Annu Rev Pharmacol Toxicol 2010; 50: 355-75.
54. Kraemer A, Rehmann HR, Cool RH, et al. Dynamic interaction of cAMP with the Rap guanine-nucleotide exchange factor Epac1. J Mol Biol 2001; 306: 1167-77.
55. Moosmang S, Biel M, Hofmann F, Ludwig A. Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Biol Chem 1999; 380: 975-80.
56. Arnsten AFT, Paspalas CD, Gamo NJ, Yang Y, Wang M. Dynamic Network Connectivity: A new form of neuroplasticity. Trends Cogn Sci. Elsevier Ltd 2010; 14: 365-75.
57. Wang M, Ramos BP, Paspalas CD, et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 2007; 129: 397-410.
58. Ramos BP, Stark D, Verduzco L, Dyck CH Van, Arnsten AFT.2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals. Learn Mem 2006; 13: 770-6.
59. Shefer V. Shefer VF. Absolute number of neurons and thickness of cerebral cortex during aging, senile and vascular dementia, and Pick’s and Alzheimer’s diseases. Neurosci Behav Physiol 1973; 6: 319-24.
60. Brody H. Organization of the cerebral cortex. III. A study of aging in the human cerebral cortex. J Comp Neurol 1955; 102: 511-6.
61. Henderson G, Tomlinson B, Gibson P. Cell counts in human cerebral cortex in normal adults throughout life, using an image analysis computer. J Neurol Sci 1980; 46: 113-36.
62. Peters A, Morrison JH, Rosene DL, Hyman BT. Are neurons lost from the primate cerebral cortex during normal aging? Cereb Cortex 1998; 8: 295-300.
63. Haug H. Are neurons of the human cerebral cortex really lost during aging? A morphometric examination. Adv Appl Neurol Sci 1985; 2: 150-63.
64. Giannaris EL, Rosene DL. A stereological study of the numbers of neurons and glia in the primary visual cortex across the lifespan of male and female rhesus monkeys. J Comp Neurol 2012; 520: 3492-508.
65. Skullerud K. Variations in the size of the human brain. Influence of age, sex, body length, body mass index, alcoholism, Alzheimer changes, and cerebral atherosclerosis. Acta Neurol Scand 1985; 102: 1-94.
66. Terry R, DeTeresa R, Hansen L. Neocortical cell counts in normal human adult aging. Ann Neurol 1987; 21: 530-9.
67. Geinisman Y. Age-related decline in memory function: is it associated with a loss of synapses? Neurobiol Aging 1999; 20: 353-6; discussion 359-60.
68. Geinisman Y, Ganeshina O, Yoshida R, Berry RW, Disterhoft JF, Gallagher M. Aging, spatial learning, and total synapse number in the rat CA1 stratum radiatum. Neurobiol Aging 2004; 25: 407-16.
69. Cruz L, Roe DL, Urbanc B, Cabral H, Stanley HE, Rosene DL. Age-related reduction in microcolumnar structure in area 46 of the rhesus monkey correlates with behavioral decline. Proc Natl Acad Sci USA 2004; 101: 15846-51.
70. Podtelezhnikov AA, Tanis KQ, Nebozhyn M, Ray WJ, Stone DJ, Loboda AP. Molecular insights into the pathogenesis of Alzheimer’s disease and its relationship to normal aging. PLoS One 2011; 6: e29610.
71. Hansen RT, Zhang H-T. Senescent-induced dysregulation of cAMP/CREB signaling and correlations with cognitive decline. Brain Res. Elsevier 2013; 1516: 93-109.
72. Glisky E. Changes in Cognitive Function in Human Aging. Brain Aging Model Methods, Mech Boca Rat CRC Press 2007; Chapter 1.
73. Herrup K. Reimagining Alzheimer’s disease--an age-based hypothesis. J Neurosci 2010; 30: 16755-62.
74. Drachman DA. Aging of the brain, entropy, and Alzheimer disease. Neurology 2006; 67: 1340-52.
75. Scheltens P, Barkhof F, Leys D, Wolters EC. Histopathologic correlates of white-matter changes on MRI in Alzheimer ’s disease and normal aging. Neurology 1995; 45: 883-8.
76. Jack CR, Petersen RC, Xu YC, et al. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer’s disease. Neurology 1997; 49: 786-94.
77. Zimmerman I, Berg A. Levels of adenosine 3’,5'-cyclic monophosphate in the cerebral cortex of aging rats. Mech Ageing Dev 1974; 3: 33-6.
78. Birkenfeld A, Ben-Zvi A. Age associated changes in intracellular cyclic adenosine monophosphate. Clin Exp Immunol 1984; 55: 651-4.
79. Austin J, Connole E, Kett D, Collins J. Studies in aging of the brain. V. Reduced norepinephrine, dopamine, and cyclic AMP in rat brain with advancing age. Age 1978; 1: 121-4.
80. Hara H, Onodera H, Kato H K. K. Effects of aging on signal transmission and transduction systems in the gerbil brain: morphological and autoradiographic study. Neuroscience 1992; 46: 475-88.
81. Sugawa M, May T. Signal transduction in aging. Arch Gerontol Geriatr 1994; 19: 235-46.
82. Delaney SM, Geiger JD. Brain regional levels of adenosine and adenosine nucleotides in rats killed by high-energy focused microwave irradiation. J Neurosci Methods 1996; 64: 151-6.
83. Murphy EJ. Brain fixation for analysis of brain lipid-mediators of signal transduction and brain eicosanoids requires head-focused microwave irradiation: an historical perspective. Prostaglandins Other Lipid Mediat. Elsevier Inc 2010; 91: 63-7.
84. WB S. Use of microwaves for rapid fixation of tissues in vivo. Scanning 1993; 15: 115-7.
85. O’Callaghan JP, Sriram K. Focused microwave irradiation of the brain preserves in vivo protein phosphorylation: comparison with other methods of sacrifice and analysis of multiple phosphoproteins. J Neurosci Methods 2004; 135: 159-68.
86. Tomobe K, Okuma Y, Nomura Y. Impairment of CREB phosphorylation in the hippocampal CA1 region of the senescenceaccelerated mouse (SAM) P8. Brain Res 2007; 1141: 214-7.
87. Kaiser LG, Schuff N, Cashdollar N, Weiner MW. Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T. Neurobiol Aging 2005; 26: 665-72.
88. O’Connor S, Scarpace P, Abrass I. Age-associated decrease of adenylate cyclase activity in rat myocardium. Mech Ageing Dev 1981; 16: 91-5.
89. Makman M, Ahn H, Thal L, et al. Evidence for selective loss of brain dopamine-and histamine-stimulated adenylate cyclase activities in rabbits with aging. Brain Res 1980; 192: 177-83.
90. Araki T, Kato H, Fujiwara T, Itoyama Y. Age-related changes in bindings of second messengers in the rat brain. Brain Res 1995; 704: 227-32.
91. Ramos BP, Birnbaum SG, Lindenmayer I, Newton SS, Duman RS, Arnsten AFT. Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron 2003; 40: 835-45.
92. Mons N, Segu L, Nogues X, Buhot M. Effects of age and spatial learning on adenylyl cyclase mRNA expression in the mouse hippocampus. Neurobiol Aging 2004; 25: 1095-106.
93. O’Connor S, Scarpace P, Abrass I. Age-associated decrease in the catalytic unit activity of rat myocardial adenylate cyclase. Mech Ageing Dev 1983; 21: 357-63.
94. Chin J, Okazaki M, Frazier J, Hu Z, Hoffman B. Impaired cAMPmediated gene expression and decreased cAMP response element binding protein in senescent cells. Am J Physiol 1996; 271: C362-71.
95. Liang C, Barnes J, Hanai H, Levine M. Decrease in Gs protein expression may impair adenylate cyclase activation in old kidneys. Am J Physiol 1993; 264: :F770-3.
96. Stancheva S, Alova L. Age-related changes of cyclic AMP phosphodiesterase activity in rat brain regions and a new phosphodiesterase inhibitor--nootropic agent adafenoxate. Gen Pharmacol 1991; 22: 955-8.
97. Harada N, Nishiyama S, Ohba H, Sato K, Kakiuchi T, Tsukada H. Age differences in phosphodiesterase type-IV and its functional response to dopamine D1 receptor modulation in the living brain: a PET study in conscious monkeys. Synapse 2002; 44: 139-45.
98. Tohda M, Murayama T, Nogiri S, Nomura Y. Influence of aging on rolipram-sensitive phosphodiesterase activity and [3H]rolipram binding in the rat brain. Biol Pharm Bull 1996; 19: 300-2.
99. O’Donnell JM, Xu Y. Evidence for global reduction in brain cyclic adenosine monophosphate signaling in depression. Biol Psychiatry 2012; 72: 524-5.
100. Liu H, Palmer D, Jimmo SL, et al. Expression of phosphodiesterase 4D (PDE4D) is regulated by both the cyclic AMP-dependent protein kinase and mitogen-activated protein kinase signaling pathways. A potential mechanism allowing for the coordinated regulation of PDE4D activity and expression. J Biol Chem 2000; 275: 26615-24.
101. D’Sa C, Tolbert LM, Conti M, Duman RS. Regulation of cAMPspecific phosphodiesterases type 4B and 4D (PDE4) splice variants by cAMP signaling in primary cortical neurons. J Neurochem 2002; 81: 745-57.
102. Laviada ID, Galve-Roperh I, Malpartida JM, Haro A. cAMP signalling mechanisms with aging in the Ceratitis capitata brain. Mech Ageing Dev 1997; 97: 45-53.
103. Blumenthal E, Malkinson A. Age-dependent changes in murine protein kinase and protease enzymes. Mech Ageing Dev 1988; 46: 201-17.
104. Jindal HK, Ai Z, Gascard P, Horton C, Cohen CM. Specific loss of protein kinase activities in senescent erythrocytes. Blood 1996; 88: 1479-87.
105. Karege F, Schwald M, Lambercy C, Murama JJ, Cisse M, Malafosse A. A non-radioactive assay for the cAMP-dependent protein kinase activity in rat brain homogenates and age-related changes in hippocampus and cortex. Brain Res 2001; 903: 86-93.
106. Karege F, Lambercy C, Schwald M, Steimer T, Cissé M. Differential changes of cAMP-dependent protein kinase activity and 3H-cAMP binding sites in rat hippocampus during maturation and aging. Neurosci Lett 2001; 315: 89-92.
107. Yamamoto-Sasaki M, Ozawa H, Saito T, Rösler M, Riederer P. Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type. Brain Res 1999; 824: 300-3.
108. Xu J, Rong S, Xie B, et al. Memory impairment in cognitively impaired aged rats associated with decreased hippocampal CREB phosphorylation: reversal by procyanidins extracted from the lotus seedpod. J Gerontol A Biol Sci Med Sci 2010; 65: 933-40.
109. Kudo K, Wati H, Qiao C, Arita J, Kanba S. Age-related disturbance of memory and CREB phosphorylation in CA1 area of hippocampus of rats. Brain Res 2005; 1054: 30-7.
110. Hattiangady B, Rao MS, Shetty GA, Shetty AK. Brain-derived neurotrophic factor, phosphorylated cyclic AMP response element binding protein and neuropeptide Y decline as early as middle age in the dentate gyrus and CA1 and CA3 subfields of the hippocampus. Exp Neurol 2005; 195: 353-71.
111. Porte Y, Buhot M-C, Mons N. Alteration of CREB phosphorylation and spatial memory deficits in aged 129T2/Sv mice. Neurobiol Aging 2008; 29: 1533-46.
112. Yin J, Wallach J, Del Vecchio M, et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 1994; 79: 49-58.
113. Brightwell JJ, Smith CA, Neve RL, Colombo PJ. Long-term memory for place learning is facilitated by expression of cAMP response element-binding protein in the dorsal hippocampus. Learn Mem 2007; 14: 195-9.
114. Johannessen M, Delghandi MP, Moens U. What turns CREB on? Cell Signal 2004; 16: 1211-27.
115. Zhao Y, Li W, Li F, et al. Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway. Biochem Biophys Res Commun 2013; 435: 597-602.
116. Martnez M, Fernandez E, Frank A, Guaza C, Hernanz A. Increased cerebrospinal fluid cAMP levels in Alzheimer ’ s disease. Brain Res 1999; 265-7.
117. Hernandez AI, Mart_nez M, Hernanz A. Increased cAMP immunostaining in cerebral vessels in Alzheimer ’ s disease. Brain Res 2001; 922: 148-52.
118. Chen Y, Huang X, Zhang Y, et al. Alzheimer’s_-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of_-amyloid. J Neurosci 2012; 32: 11390-5.
119. Cowburn R, O’Neill C, Ravid R, Alafuzoff I, Winblad B, Fowler C. Adenylyl cyclase activity in postmortem human brain: evidence of altered G protein mediation in Alzheimer’s disease. J Neurochem 1992; 58: 1409-19.
120. O’Neill C, Wiehager B, Fowler C, Ravid R, Winblad B, Cowburn R. Regionally selective alterations in G protein subunit levels in the Alzheimer’s disease brain. Brain Res 1994; 636: 193-201.
121. Ohm T, Bohl J, Lemmer B. Reduced cAMP-signal transduction in postmortem hippocampus of demented old people. Prog Clin Biol Res 1989; 317: 501-9.
122. Ohm T, Bohl J, Lemmer B. Reduced basal and stimulated (isoprenaline, Gpp(NH)p, forskolin) adenylate cyclase activity in Alzheimer’s disease correlated with histopathological changes. Brain Res 1991; 540: 229-36.
123. Schnecko A, Witte K, Bohl J, Ohm T, Lemmer B. Adenylyl cyclase activity in Alzheimer’s disease brain: stimulatory and inhibitory signal transduction pathways are differently affected. Brain Res 1994; 644: 291-6.
124. Yamamoto M, Go ME, Ozawa H, et al. Hippocampal level of neural specific adenylyl cyclase type I is decreased in Alzheimer ’ s disease. Biochim Biophys Acta 2000; 1535: 60-8.
125. Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW. Incipient Alzheimer’s disease_: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses 2003;
126. Schwabe U, Miyake M, Ohga Y, Daly JW. 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62711): a potent inhibitor of adenosine cyclic 3_,5_-monophosphate phosphodiesterases in homogenates and tissue slices from rat brain. Mol Pharmacol 1976; 12: 900-10.
127. 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 USA 2002; 99: 13217-21.
128. McLachlan C, Chen M, Lynex C, Goh D, Brenner S, Tay S. Changes in PDE4D Isoforms in the Hippocampus of a Patient With Advanced Alzheimer Disease. Arch Neurol 2013; 64: 456-7.
129. Pérez-Torres S, Mengod G. cAMP-specific phosphodiesterases expression in Alzheimer’s disease brains. Int Congr Ser 2003; 1251: 127-38.
130. Gygi SP, Rochon Y, Franza BR, Aebersold R. Correlation between Protein and mRNA Abundance in Yeast Correlation between Protein and mRNA Abundance in Yeast. Mol Cell Biol 1999; 19: 1720.
131. Sebastiani G, Morissette C, Lagacé C, et al. The cAMP-specific phosphodiesterase 4B mediates Abeta-induced microglial activation. Neurobiol Aging 2006; 27: 691-701.
132. Pugazhenthi S, Wang M, Pham S, Sze C, Eckman CB. Downregulation of CREB expression in Alzheimer ’ s brain and in A beta-treated rat hippocampal neurons. Mol Neurodegener. BioMed Central Ltd 2011; 6: 60.
133. Wang C, Yang XM, Zhuo YY, et al. The phosphodiesterase-4 inhibitor rolipram reverses A_-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats. Int J Neuropsychopharmacol 2012; 15: 749-66.
134. Ikezu T, Okamoto T, Komatsuzakil K, Matsui T, Martyn JAJ, Nishimoto I. Negative transactivation of cAMP response element by familial Alzheimer ’ s mutants of APP. EMBO J 1996; 15: 2468-75.
135. Giambarella U, Murayama Y, Ikezu T, Fujita T, Nishimoto I. Potential CRE suppression by familial Alzheimer’s mutants of APP independent of adenylyl cyclase regulation. FEBS Lett. Federation of European Biochemical Societies 1997; 412: 97-101.
136. Müller M, Cárdenas C, Mei L, Cheung K-H, Foskett JK. Constitutive cAMP response element binding protein (CREB) activation by Alzheimer’s disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling. Proc Natl Acad Sci USA 2011; 108: 13293-8.
137. Echeverria V, Ducatenzeiler A, Chen CH, Cuello AC. Endogenous beta-amyloid peptide synthesis modulates cAMP response elementregulated gene expression in PC12 cells. Neuroscience 2005; 135: 1193-202.
138. Arvanitis DN, Ducatenzeiler A, Ou JN, et al. High intracellular concentrations of amyloid-beta block nuclear translocation of phosphorylated CREB. J Neurochem 2007; 103: 216-28.
139. Satoh J, Tabunoki H, Arima K. Molecular network analysis suggests aberrant CREB-mediated gene regulation in the Alzheimer disease hippocampus. Dis Markers 2009; 27: 239-52.
140. Frankola KA, Greig NH, Luo W, Tweedie D. Targeting TNF-α to elucidate and ameliorate neuroinflammation in neurodegenerative diseases. CNS Neurol Disord Drug Targets 2011; 10: 391-403.
141. Clark I, Atwood C, Bowen R, Paz-Filho G, Vissel B. Tumor necrosis factor-induced cerebral insulin resistance in Alzheimer’s disease links numerous treatment rationales. Pharmacol Rev 2012; 64: 1004-26.
142. Montgomery SL, Bowers WJ. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol 2012; 7: 42-59.
143. Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientificWorldJournal 2012; 2012: 756357.
144. Galimberti D, Scarpini E. Inflammation and oxidative damage in Alzheimer’s disease: friend or foe? Front Biosci (Schol Ed) 2011; 3: 252-66.
145. Gong B, Vitolo O V, 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: 1624-34.
146. Cheng Y-F, Wang C, Lin H-B, et al. Inhibition of phosphodiesterase-4 reverses memory deficits produced by A_25-35 or A_1-40 peptide in rats. Psychopharmacology (Berl) 2010; 212: 181-91.
147. Mori F, Pérez-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.
148. Sierksma ASR, van den Hove DLA, Pfau F, et al. Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D. Neuropharmacology. Elsevier Ltd 2013; 1-12.
149. Zhang C, Cheng Y, Wang H, Wang C, Xu J, Zhang H. RNA Interference-Mediated Knockdown of Long-Form Phosphodiesterase-4D (PDE4D) Enzyme Reverses Amyloid-_42-Induced Memory Deficits in Mice. J Alzheimers Dis 2013; [Epub ahea.
150. 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 USA 2009; 106: 16877-82.
151. Yiu AP, Rashid AJ, Josselyn SA. Increasing CREB function in the CA1 region of dorsal hippocampus rescues the spatial memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology. Nature Publishing Group 2011; 36: 2169-86.
152. Han W-N, Hölscher C, Yuan L, et al. Liraglutide protects against amyloid-_protein-induced impairment of spatial learning and memory in rats. Neurobiol Aging 2013; 34: 576-88.
153. Rutten K, Van Donkelaar EL, Ferrington L, et al. Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats. Neuropsychopharmacology. Nature Publishing Group 2009; 34: 1914-25.
154. De Lima MN, Presti-Torres J, Garcia VA, et al. Amelioration of recognition memory impairment associated with iron loading or aging by the type 4-specific phosphodiesterase inhibitor rolipram in rats. Neuropharmacology 2008; 55: 788-92.
155. Tredici G, Miloso M, Nicolini G, Galbiati S, Cavaletti G, Bertelli A. Resveratrol, map kinases and neuronal cells: might wine be a neuroprotectant? Drugs Exp Clin Res 1999; 25: 99-103.
156. Park S-J, Ahmad F, Philp A, et al. Resveratrol ameliorates agingrelated metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell. Elsevier Inc 2012; 148: 421-33.
157. Roscioni SS, Elzinga CRS, Schmidt M. Epac : effectors and biological functions. Prostaglandins 2008; 377: 345-57.
158. Ouyang M, Zhang L, Zhu JJ, Schwede F, Thomas SA. Epac signaling is required for hippocampus-dependent memory retrieval. Proc Natl Acad Sci USA 2008; 105: 11993-7.
159. Murray AJ, Shewan DA. Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration. Mol Cell Neurosci 2008; 38: 578-88.
160. Murray AJ, Tucker SJ, Shewan DA. cAMP-dependent axon guidance is distinctly regulated by Epac and protein kinase A. J Neurosci 2009; 29: 15434-44.
161. Kim D, Nguyen MD, Dobbin MM, et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J 2007; 26: 3169-79.
162. Cristòfol R, Porquet D, Corpas R, et al. Neurons from senescenceaccelerated SAMP8 mice are protected against frailty by the sirtuin 1 promoting agents melatonin and resveratrol. J Pineal Res 2012; 52: 271-81.
163. Mcphee I, Gibson LC, Kewney J, et al. Cyclic nucleotide signalling: A molecular approach to drug discovery for Alzheimer’s disease. Biochem Soc Trans 2005; 33: 1330-2.
164. Maillet M, Robert SJ, Cacquevel M, et al. Crosstalk between Rap1 and Rac regulates secretion of sAPPalpha. Nat Cell Biol 2003; 5: 633-9.
165. Zaldua N, Gastineau M, Hoshino M, Lezoualc’h F, Zugaza JL. Epac signaling pathway involves STEF, a guanine nucleotide exchange factor for Rac, to regulate APP processing. Sci Technol 2007; 581: 5814-8.
166. Scott A, Perini A, Shering P, Whalley L. In-patient major depression: is rolipram as effective as amitriptyline? Eur J Clin Pharmacol 1991; 40: 127-9.
167. Catherine Jin S-L, Bushnik T, Lan L, Conti M. Subcellular Localization of Rolipram-sensitive, cAMP-specific Phosphodiesterases. Differential Targeting and Activation of The Splicing Variants Derived From The PDE4D Gene. J Biol Chem 1998; 273: 19672-8.
168. Martin ACL, Cooper DMF. Layers of organization of cAMP microdomains in a simple cell. Biochem Soc Trans 2006; 34: 480-3.
169. Blackman B, Horner K, Heidmann J, et al. PDE4D and PDE4B Function in Distinct Subcellular Compartments in Mouse Embryonic Fibroblasts. J Biol Chem 2011; 286: 12590-601.
170. Oliveira RF, Terrin A, Di Benedetto G, et al. The role of type 4 phosphodiesterases in generating microdomains of cAMP: large scale stochastic simulations. PLoS One 2010; 5: e11725.
171. Baillie GS. Compartmentalized signalling: spatial regulation of cAMP by the action of compartmentalized phosphodiesterases. FEBS J 2009; 276: 1790-9.
172. Vincent P, Castro LR V, Gervasi N, Guiot E, Brito M, Paupardin-Tritsch D. PDE4 control on cAMP/PKA compartmentation revealed by biosensor imaging in neurons. Horm Metab Res 2012; 44: 786-9.
173. Mulchahey JJ, Regmi A, Sheriff S, Balasubramaniam A, Kasckow JW. Coordinate and divergent regulation of corticotropin-releasing factor (CRF) and CRF-binding protein expression in an immortalized amygdalar neuronal cell line. Endocrinology 1999; 140: 251-9.
174. Sheriff S, Dautzenberg FM, Mulchahey JJ, et al. Interaction of neuropeptide Y and corticotropin-releasing factor signaling pathways in AR-5 amygdalar cells. Peptides 2001; 22: 2083-9.
175. Adamec R, Hebert M, Blundell J. Long lasting effects of predator stress on pCREB expression in brain regions involved in fearful and anxious behavior. Behav Brain Res. Elsevier B.V 2011; 221: 118-33.
176. Lakshminarasimhan H, Chattarji S. Stress leads to contrasting effects on the levels of brain derived neurotrophic factor in the hippocampus and amygdala. PLoS One 2012; 7: e30481.
177. Wallace TL, Stellitano KE, Neve RL, Duman RS. Effects of cyclic adenosine monophosphate response element binding protein overexpression in the basolateral amygdala on behavioral models of depression and anxiety. Biol Psychiatry 2004; 56: 151-60.
178. Muschamp JW, Van’t Veer A, Parsegian A, et al. Activation of CREB in the Nucleus Accumbens Shell Produces Anhedonia and Resistance to Extinction of Fear in Rats. J Neurosci 2011; 31: 3095-103.
179. Taylor JR, Birnbaum S, Ubriani R, Arnsten AF. Activation of cAMP-dependent protein kinase A in prefrontal cortex impairs working memory performance. J Neurosci 1999; 19: RC23.
180. Wang M, Gamo NJ, Yang Y, et al. Neuronal Basis of Age-Related Working Memory Decline. Nature 2012; 476: 210-3.
181. Arnsten AFT, Ramos BP, Birnbaum SG, Taylor JR. Protein kinase A as a therapeutic target for memory disorders: rationale and challenges. Trends Mol Med 2005; 11: 121-8.
182. Arnsten AFT, Jin LE. Guanfacine for the treatment of cognitive disorders: A century of discoveries at Yale. Yale J Biol Med 2012; 85: 45-58.
183. Vandesquille M, Baudonnat M, Decorte L, Louis C, Lestage P, Béracochéa D. Working memory deficits and related disinhibition of the cAMP/PKA/CREB are alleviated by prefrontal_4_2*-nAChRs stimulation in aged mice. Neurobiol Aging 2013; 34: 1599-609.
184. Garelick MG, Chan GCK, DiRocco DP, Storm DR. Overexpression of type I adenylyl cyclase in the forebrain impairs spatial memory in aged but not young mice. J Neurosci 2009; 29: 10835-42.
185. Canepa E, Domenicott IC, Marengo B, et al. Cyclic adenosine monophosphate as an endogenous modulator of the amyloid-_precursor protein metabolism. IUBMB Life 2013; 65: 127-33.
186. Litersky JM, Johnson GV. Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain. J Biol Chem 1992; 267: 1563-8.
187. Jicha GA, Weaver C, Lane E, et al. cAMP-Dependent Protein Kinase Phosphorylations on Tau in Alzheimer’s Disease. J Neurosci 1999; 19: 7486-94.