Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment

Gong, Bing; Vitolo, Ottavio V.; Trinchese, Fabrizio; Liu, Shumin; Shelanski, Michael; Arancio, Ottavio

doi:10.1172/jci22831

Cited by 452Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

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Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment

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Gong, Bing, Vitolo, Ottavio V., Trinchese, Fabrizio, Liu, Shumin, Shelanski, Michael, Arancio, Ottavio·2004·Journal of Clinical Investigation

DOI 10.1172/jci22831PMC PMC529285

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Abstract

Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid beta-peptide 1-42 (Abeta42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Abeta. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Abeta42 levels.

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Transgenic mouse AD models manifest a spontaneous age-onset impairment of LTP that presumably is linked to impaired performance in memory tests.
“Tg-mouse AD models manifest a spontaneous age-onset impairment of LTP (Gong et al., 2004) that presumably is linked to impaired performance in memory tests (Arendash et al., 2001).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Gong et al., 2004

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Dysregulation of Histone Acetylation in the APP/PS1 Mouse Model of Alzheimer's Disease
Francis, Y. I., Fà, M., Ashraf, H., Zhang, H., Staniszewski, A., Latchman, D. S., & Arancio, O. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1134 · Cited by 306
“Next, we asked whether HDAC inhibition was also capable of ameliorating the associative memory deﬁcit observed in the APP/PS1 mouse [24].”
Influential
Selective phosphodiesterase inhibitors: a promising target for cognition enhancement
Reneerkens, O. A. H., Rutten, K., Steinbusch, H. W. M., Blokland, A., & Prickaerts, J. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1273-x · Cited by 271
“, PS1/PDAPP KO mice in the radial arm water maze (Costa et al. 2007; Gong et al. 2004).”
BackgroundMethodInfluential
Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease
García‐Osta, A., Cuadrado‐Tejedor, M., García, C., Oyarzábal, J., & Franco, R. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn3000907 · Cited by 264
Lymphatic drainage system of the brain: A novel target for intervention of neurological diseases
Sun, B., Wang, L.-H., Yang, T., Sun, J., Mao, L., Yang, M., Yuan, H., Colvin, R. A., & Yang, X. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.08.007 · Cited by 263
Brain Slices as Models for Neurodegenerative Disease and Screening Platforms to Identify Novel Therapeutics
Cho, S., Wood, A., & Bowlby, M. R. (2007) · Current Neuropharmacology · doi:10.2174/157015907780077105 · Cited by 247
“In addition, many other mechanisms have been demonstrated to enhance synaptic transmission and/or plasticity in models showing such deficits, thus leading to multiple hypotheses regarding potential cognitive enhancers in AD [40, 67, 118, 169].”
Background
Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease
Ricobaraza, A., Cuadrado‐Tejedor, M., Marco, S., Pérez‐Otaño, I., & García‐Osta, A. (2012) · Hippocampus · doi:10.1002/hipo.20883 · Cited by 239
“The latter include treatments that potentiate CREB signaling pathways (Gong et al., 2004; Smith et al., 2009) and modulators of chromatin structure (Ricobaraza et al., 2009; Kilgore et al., 2010).”
Background
Reversal of long-term dendritic spine alterations in Alzheimer disease models
Smith, D. L., Pozueta, J., Gong, B., Arancio, O., & Shelanski, M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908706106 · Cited by 229
“APP/PS1 mice display impaired LTP, spatial working memory, and contextual learning as early as 3–4 months of age, and they show deficits in basal synaptic transmission (BST) and spatial reference memory after 5–6 months of age (6).”
Background
Downregulation of CREB expression in Alzheimer's brain and in Aβ-treated rat hippocampal neurons
Pugazhenthi, S., Wang, M., Pham, S. T., Sze, C., & Eckman, C. B. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-60 · Cited by 245
“Previous studies have suggested that markers of CREB function are downregulated in the hippocampal neurons of this mouse model [14,15,29].”
Background
Rodent models for Alzheimer’s disease drug discovery
Puzzo, D., Gulisano, W., Palmeri, A., & Arancio, O. (2015) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2015.1041913 · Cited by 222
“In particular, mice overexpressing APP (K670N:M671L) together with PS1 (M146L) have been extensively used to better understand the pathogenic mechanisms underlying synaptic dysfunction and memory loss in AD, and to validate new therapeutic approaches [35-46].”
BackgroundSelf-citation
Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms
Costa, D. A., Cracchiolo, J. R., Bachstetter, A. D., Hughes, T. F., Bales, K. R., Paul, S. M., Mervis, R. F., Arendash, G. W., & Potter, H. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.04.009 · Cited by 226
“The PDE4 inhibitor, Rolipram, has been found to alleviate memory deficits in rodent models, including transgenic mice [6,7,23].”
Behavioral assays with mouse models of Alzheimer's disease: Practical considerations and guidelines
Puzzo, D., Lee, L. S., Palmeri, A., Calabrese, G., & Arancio, O. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.011 · Cited by 227
“2) mice [83,138,140] as demonstrated by the increased number of errors at A4 and R compared with WT littermates.”
BackgroundMethodInfluential
Exercise improves cognition and hippocampal plasticity in APOE ɛ4 mice
Nichol, K., Deeny, S. P., Seif, J., Camaclang, K., & Cotman, C. W. (2009) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2009.02.006 · Cited by 213
“We measured both time to find platforms (latency), and entries of nontarget arms (errors), although errors were shown to be more sensitive to dysfunction [29,30].”
Acute γ-Secretase Inhibition Improves Contextual Fear Conditioning in the Tg2576 Mouse Model of Alzheimer's Disease
Comery, T. A., Martone, R. L., Aschmies, S., Atchison, K. P., Diamantidis, G., Gong, X., Zhou, H., Kreft, A. F., Pangalos, M. N., Sonnenberg‐Reines, J., et al. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2693-05.2005 · Cited by 214
“In vivo, rolipram has been demonstrated to ameliorate the cognitive deficits induced by scopolamine as well as improve retention in cognitively intact animals and other AD transgenic models using contextual fear conditioning (Barad et al., 1998; Zhang and O’Donnell, 2000; Gong et al., 2004).”
Background
Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease
Cuadrado‐Tejedor, M., Hervías, I., Ricobaraza, A., Puerta, E., Pérez-Roldán, J., García, C., Franco, R., Aguirre, N., & García‐Osta, A. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01517.x · Cited by 209
“Other studies have also failed in finding a correlation between a decrease in deposited forms of Ab (such as plaques) and memory improvement in Alzheimer’s disease models (Dodart et al., 2002; Gong et al., 2004; Malm et al., 2007; Ricobaraza et al., 2009).”
Background
Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease
Trinchese, F., Fà, M., Liu, S., Zhang, H., Hidalgo, A., Schmidt, S. D., Yamaguchi, H., Yoshii, N., Mathews, P. M., Nixon, R. A., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34254 · Cited by 209
“Studies on AD mouse models and on slices exposed to sublethal levels of Aβ42 have shown reduced levels of pCREB, a transcriptional mediator of LTP and memory (19, 20, 47, 49).”
Brain-Targeted Proanthocyanidin Metabolites for Alzheimer's Disease Treatment
Wang, J., Ferruzzi, M. G., Ho, L., Blount, J. W., Janle, E. M., Gong, B., Pan, Y., Gowda, G. A. N., Raftery, D., Arrieta‐Cruz, I., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.6437-11.2012 · Cited by 210
“The field EPSPs (fEPSPs) were recorded from the CA1 region as described previously (Gong et al., 2004).”
Identification of brain‐targeted bioactive dietary quercetin‐3‐ O ‐glucuronide as a novel intervention for Alzheimer's disease
Ho, L., Ferruzzi, M. G., Janle, E. M., Wang, J., Gong, B., Chen, T., Lobo, J., Cooper, B. R., Wu, Q. L., Talcott, S. T., et al. (2012) · The FASEB Journal · doi:10.1096/fj.12-212118 · Cited by 206
Chapter 6 Regulation of hippocampus-dependent memory by cyclic AMP-dependent protein kinase
Abel, T., & Nguyen, P. V. (2008) · Progress in Brain Research · doi:10.1016/s0079-6123(07)00006-4 · Cited by 198
“Interestingly, these PDE inhibitors can reverse the memory impairments found in aged mice (Bach et al., 1999) and in mouse models of mental retardation (Bourtchouladze et al., 2003) and Alzheimer’s Disease (Vitolo et al., 2002; Gong et al., 2004).”
Background
Neurotrophins, synaptic plasticity and dementia
Arancio, O., & Chao, M. V. (2007) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2007.03.013 · Cited by 156
Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism
Berman, D. E., Dall'Armi, C., Voronov, S. V., McIntire, L. B. J., Zhang, H., Moore, A. Z., Staniszewski, A., Arancio, O., Kim, T.-W., & Di Paolo, G. (2008) · Nature Neuroscience · doi:10.1038/nn.2100 · Cited by 199
“Morris water-maze experiments were carried out according to a published procedur”
Method
The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents
van der Staay, F. J., Rutten, K., Bärfacker, L., DeVry, J., Erb, C., Heckroth, H., Karthaus, D., Tersteegen, A., van Kampen, M., Blokland, A., et al. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.07.005 · Cited by 180
“Moreover, it has been proposed that inhibition of PDE4 activity in particular might effectively counteract the learning and memory deﬁcits of patients suffering from Alzheimer’s disease (AD) (Gong et al., 2004).”
Environmental Novelty Activates β2-Adrenergic Signaling to Prevent the Impairment of Hippocampal LTP by Aβ Oligomers
Li, S., Jin, M., Zhang, D., Yang, T., Koeglsperger, T., Fu, H., & Selkoe, D. J. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.040 · Cited by 189
Lysine Acetyltransferases CBP and p300 as Therapeutic Targets in Cognitive and Neurodegenerative Disorders
Valor, L. M., Viosca, J., López‐Atalaya, J. P., & Barco, Á. (2013) · Current Pharmaceutical Design · doi:10.2174/13816128113199990382 · Cited by 173
“There is also evidence, including amelioration of learning impairments [186, 192], that this compound is beneficial in AD animal models.”
Background
The expanding role of BDNF: a therapeutic target for Alzheimer's disease?
Fumagalli, F., Racagni, G., & Riva, M. A. (2005) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500337 · Cited by 173
Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease
Prickaerts, J., Heckman, P. R. A., & Blokland, A. (2017) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2017.1364360 · Cited by 172
“The latter was also reported in previous studies with the classic PDE4 inhibitor rolipram, yet it rescued decreased CREB activation [73,74].”
Result
The Ubiquitin-Proteasome System: Potential Therapeutic Targets for Alzheimer’s Disease and Spinal Cord Injury
Gong, B., Radulovic, M., Figueiredo‐Pereira, M. E., & Cardozo, C. P. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00004 · Cited by 176
Long-term green tea catechin administration prevents spatial learning and memory impairment in senescence-accelerated mouse prone-8 mice by decreasing Aβ1-42 oligomers and upregulating synaptic plasticity–related proteins in the hippocampus
Li, Q., Zhao, H., Zhang, Z. F., Liu, Z. G., Pei, X., Wang, J. B., & Li, Y. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.07.014 · Cited by 165
Sex Differences in Neuropathology and Cognitive Behavior in APP/PS1/tau Triple-Transgenic Mouse Model of Alzheimer’s Disease
Yang, J., Wang, Z., Cai, H.-Y., Li, Y., Hu, M.-M., Wu, M., & Qi, J. (2018) · Neuroscience Bulletin · doi:10.1007/s12264-018-0268-9 · Cited by 168
Multi-faced neuroprotective effects of Ginsenoside Rg1 in an Alzheimer mouse model
Fang, F., Chen, X., Huang, T., Lue, L., Luddy, J. S., & Yan, S. S. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.10.004 · Cited by 161
“It has been proposed that the effect of Aβ on long term potentiation (a form of synaptic function) and memory is mediated by the inhibition of phosphorylation of CREB, a transcription factor that is activated by cAMPdependent protein kinase (PKA) activity[29, 33].”
Influential
Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome
Voronov, S. V., Frere, S. G., Giovedi, S., Pollina, E. A., Borel, C., Zhang, H., Schmidt, C., Akeson, E. C., Wenk, M. R., Cimasoni, L., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803756105 · Cited by 174
“The Morris water maze was performed as described (42) with some modifications in the hidden platform test.”
Method
Etazolate, a neuroprotective drug linking GABAA receptor pharmacology to amyloid precursor protein processing
Marcade, M., Bourdin, J., Loiseau, N., Peillon, H., Rayer, A., Drouin, D., Schweighoffer, F., & Désiré, L. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05396.x · Cited by 155
“By stimulating cAMP levels, the PDE4 inhibitor Rolipram and the PDE4CREB pathway show beneficial effect at counteracting Abinduced memory, synaptic and dendritic alterations (Gong et al. 2004; Shrestha et al. 2006).”
Background
Ibudilast (AV-411)
Ledeboer, A., Hutchinson, M. R., Watkins, L. R., & Johnson, K. W. (2007) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.16.7.935 · Cited by 153
“Indeed, the prototypical PDE4 inhibitor rolipram exhibits efficacy in animal models of Alzheimer’s disease [87] , multiple sclerosis (MS) [88] and spinal cord injury [89] .”
Background
Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice
Zhang, J., Guo, J., Zhao, X., Chen, Z., Wang, G., Liu, A., Wang, Q., Zhou, W., Xu, Y., & Wang, C. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.05.017 · Cited by 153
Cyclic nucleotide signaling changes associated with normal aging and age-related diseases of the brain
Kelly, M. P. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.11.004 · Cited by 147
The phosphodiesterase-4 inhibitor rolipram reverses Aβ-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats
Wang, C., Yang, X., Zhuo, Y., Zhou, H., Lin, H.-B., Cheng, Y., Xu, J., & Zhang, H. (2011) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711000836 · Cited by 150
“This is supported by findings in the study using APP/PS1 transgenic mice (Gong et al. 2004) and in our previous study, in which rolipram administered at 0.”
BackgroundResultInfluential
PDE4 as a target for cognition enhancement
Richter, W., Menniti, F. S., Zhang, H., & Conti, M. (2013) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2013.818656 · Cited by 148
“Mechanistically, PDE4 inactivation serves to enhance LTP as well as promote synaptic plasticity [30,49,50,57,58].”
Influential
Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer’s disease
Branca, C., Ferreira, E., Nguyen, T.-V., Doyle, K., Caccamo, A., & Oddo, S. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx361 · Cited by 139
“contextual fear conditioning (48,49), while others have found”
Background
Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach
Teich, A. F., Nicholls, R. E., Puzzo, D., Fiorito, J., Purgatorio, R., Fà, M., & Arancio, O. (2015) · Neurotherapeutics · doi:10.1007/s13311-014-0327-5 · Cited by 151
“displays impaired synaptic plasticity and memory as early as 3–4 months of age [26], and our group has found that rolipram rescues LTP, contextual fear conditioning, and spatial working memory in these mice [27].”
Background
Modulation of the cAMP signaling pathway after traumatic brain injury
Atkins, C. M., Oliva, A. A., Alonso, O. F., Pearse, D. D., Bramlett, H. M., & Dietrich, W. D. (2007) · Experimental Neurology · doi:10.1016/j.expneurol.2007.08.011 · Cited by 140
“Rolipram has also been found to improve outcome in experimental allergic encephalomyelitis, Alzheimer disease, multiple sclerosis, ischemia, and striatal excitotoxicity (Genain et al., 1995, Navikas et al., 1998, Folcik et al., 1999, Gong et al., 2004, Demarch et al., 2007, Sasaki et al., 2007).”
Background
GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses
Bruno, O., Fedele, E., Prickaerts, J., Parker, L. A., Canepa, E., Brullo, C., Cavallero, A., Gardella, E., Balbi, A., Domenicotti, C., et al. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01524.x · Cited by 137
Hippocampal synaptic plasticity in Alzheimer’s disease: what have we learned so far from transgenic models?
Marchetti, C., & Marie, H. (2011) · Reviews in the Neurosciences · doi:10.1515/rns.2011.035 · Cited by 141
Nobiletin restoring β-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer's disease model rats
Matsuzaki, K., Yamakuni, T., Hashimoto, M., Haque, A. M., Shido, O., Mimaki, Y., Sashida, Y., & Ohizumi, Y. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2006.02.077 · Cited by 135
Down‐regulation of cAMP‐dependent protein kinase by over‐activated calpain in Alzheimer disease brain
Liang, Z., Liu, F., Grundke, I., Iqbal, K., & Gong, C. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04942.x · Cited by 133
“In AD brain and some mouse models of AD, CREB activity is impaired (Yamamoto-Sasaki et al. 1999; Gong et al. 2004; Puzzo et al. 2005; Matsuzaki et al. 2006), but the mechanisms leading to the CREB dysregulation are unknown.”
Background
Spines, plasticity, and cognition in Alzheimer's model mice
Spires-Jones, T., & Knafo, S. (2012) · Neural Plasticity · doi:10.1155/2012/319836 · Cited by 133
“6–12 Impaired [79, 80, 105, 126– 128, 134] Normal [105, 127, 134]/impaired [79, 80, 126, 128] Impaired [80, 127, 129, 130] Impaired [79]/normal [127]”
FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP/PS1 transgenic mice via cAMP/PKA/CREB signaling and anti-inflammatory effects
Guo, H., Cheng, Y., Wang, C., Wu, J., Zou, Z., Niu, B., Yu, H. M., Wang, H., & Xu, J. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.01.004 · Cited by 133
“Our results were consistent with other PDE4 inhibitor researches by (Gong et al., 2004; Sierksma et al., 2014).”
Influential
Rolipram reverses scopolamine-induced and time-dependent memory deficits in object recognition by different mechanisms of action
Rutten, K., Prickaerts, J., & Blokland, A. (2005) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2005.09.002 · Cited by 132
“Accordingly, a substantial amount of studies have shown a positive eVect of PDE4 inhibition on spatial memory (Bach et al., 1999; Gong et al., 2004; Nagakura, Niimura, & Takeo, 2002), inhibitory avoidance learning (Egawa, Mishima, Matsumoto, Iwasaki, & Fujiwara, 1997; Ghelardini et al., 2002;…”
Background
Alzheimer's β-Secretase (BACE1) Regulates the cAMP/PKA/CREB Pathway Independently of β-Amyloid
Chen, Y., Huang, X., Zhang, Y.-W., Rockenstein, E., Bu, G., Golde, T. E., Masliah, E., & Xu, H. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.0757-12.2012 · Cited by 117
“CREB-mediated gene expression is impaired in the brains of both AD mouse models and patients (Phillips et al., 1991; Gong et al., 2004), as well as in cultured neurons insulted with A (Tong et al., 2001).”
Background
Novel Phosphodiesterase Inhibitors for Cognitive Improvement in Alzheimer’s Disease
Wu, Y., Li, Z., Huang, Y., Wu, D., & Luo, H. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01370 · Cited by 129
-Amyloid Disrupts Activity-Dependent Gene Transcription Required for Memory through the CREB Coactivator CRTC1
España, J., Valero, J., Miñano-Molina, A. J., Masgrau, R., Martín, E., Guardia‐Laguarta, C., Lleó, A., Giménez‐Llort, L., Rodrı́guez-Álvarez, J., & Saura, C. A. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.2154-10.2010 · Cited by 137
“Disruption of CRTC1-dependent gene expression is associated with hippocampal-dependent memory deficits in APPSwe,Ind transgenic mice Having seen the critical role of A on CRTC1-mediated transcription, we finally analyzed its effect on memory deficits in APPSw,Ind transgenic mice at an age (6…”
BackgroundInfluential
Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer's disease-experimental approach and therapeutic implications
Wang, J., Bi, W., Cheng, A., Freire, D., Vempati, P., Zhao, W., Gong, B., Janle, E. M., Chen, T., Ferruzzi, M. G., et al. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00042 · Cited by 128
Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D
Sierksma, A. S. R., van den Hove, D., Pfau, F., Philippens, M., Bruno, O., Fedele, E., Ricciarelli, R., Steinbusch, H. W. M., Vanmierlo, T., & Prickaerts, J. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.09.015 · Cited by 132
“Similarly, rolipram treatment could elevate cAMP levels and improve spatial memory performance in AD mice, without affecting Ab production or deposition (Vitolo et al., 2002; Gong et al., 2004).”
BackgroundResultInfluential
The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain
Ledeboer, A., Liu, T., Shumilla, J. A., Mahoney, J. H., Vijay, S., Gross, M. I., Vargas, J. A., Sultzbaugh, L., Claypool, M. D., Sanftner, L. M., et al. (2006) · Neuron Glia Biology · doi:10.1017/s1740925x0700035x · Cited by 122
“In other animal models, the PDE4 inhibitor rolipram is effective in arthritis (Francischi et al., 2000), spinal cord injury (Nikulina et al., 2004), EAE (Genain et al., 1995; Sommer et al., 1995; Jung et al., 1996) and Alzheimer’s disease (Gong et al., 2004; Comery et al., 2005).”
Background
Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations
Maramai, S., Benchekroun, M., Gabr, M. T., & Yahiaoui, S. (2020) · BioMed Research International · doi:10.1155/2020/5120230 · Cited by 121
“They proposed hybrid compounds merging the metal ion chelating framework of chloroquine and the key binding site fragments of the known PDE4 inhibitors Rolipram and Roflumilast, already tested in preclinical models of AD [132] (see also NCT01433666 and NCT02051335).”
Background
Phosphodiesterase-4 (PDE4) Molecular Pharmacology and Alzheimer's Disease
Gurney, M. E., D'Amato, E. C., & Burgin, A. B. (2015) · Neurotherapeutics · doi:10.1007/s13311-014-0309-7 · Cited by 121
Current therapeutic targets for the treatment of Alzheimer’s disease
Grill, J. D., & Cummings, J. L. (2010) · Expert Review of Neurotherapeutics · doi:10.1586/ern.10.29 · Cited by 123
Enhanced long‐term potentiation and impaired learning in phosphodiesterase 4D‐knockout (PDE4D−/−) mice
Rutten, K., Misner, D., Works, M. G., Blokland, A., Novak, T. J., Santarelli, L., & Wallace, T. L. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06349.x · Cited by 114
“PDE4 inhibitors have also been shown to reverse memory impairments in genetic mouse models of human disorders, including Rubinstein–Taybi syndrome (Bourtchouladze et al., 2003) and Alzheimer’s disease (Gong et al., 2004; Comery et al., 2005).”
Background
Advances in the Development of Phosphodiesterase-4 Inhibitors
Peng, T., Qi, B., He, J., Ke, H., & Shi, J. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02170 · Cited by 118
Stimulation of PGE2 receptors EP2 and EP4 protects cultured neurons against oxidative stress and cell death following β‐amyloid exposure
Echeverrı́a, V., Clerman, A., & Doré, S. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04427.x · Cited by 122
“nervous system, improved synaptic and cognitive functions in a mouse AD model (Gong et al., 2004).”
BackgroundResult
Mitochondrial Mislocalization Underlies Aβ42-Induced Neuronal Dysfunction in a Drosophila Model of Alzheimer's Disease
Iijima‐Ando, K., Hearn, S., Shenton, C., Gatt, A., Zhao, L., & Iijima, K. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008310 · Cited by 126
“For example, rolipram, the most widely used PDE4 inhibitor, ameliorates memory impairments in APP-PSEN1 double transgenic mice [56].”
Background
Beneficial effects of rolipram in the R6/2 mouse model of Huntington's disease
DeMarch, Z., Giampà, C., Patassini, S., Bernardi, G., & Fusco, F. R. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.02.010 · Cited by 121
(−)-Epigallocatechin-3-Gallate Ameliorates Learning and Memory Deficits by Adjusting the Balance of TrkA/p75NTR Signaling in APP/PS1 Transgenic Mice
Liu, M., Chen, F., Sha, L., Wang, S., Lin, T., Yao, L., He, M., Yao, Z., Liu, H., Zhu, Z., et al. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8608-2 · Cited by 117
“The activation and phosphorylation of CREB also inhibit the Aβ oligomerization and formation and decrease the Aβ neurotoxicity [45, 46].”
Background
Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats
Rutten, K., van Donkelaar, E. L., Ferrington, L., Blokland, A., Bollen, E., Steinbusch, H. W. M., Kelly, P. A., & Prickaerts, J. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2009.24 · Cited by 114
“…CNS diseases, including Alzheimer's disease, schizophrenia, and affective disorders and have recently been proposed as potential targets for therapeutic intervention (Gong et al, 2004; Halene and Siegel 2007; Maxwell et al, 2004; Menniti et al, 2007; Reyes-Irisarri et al, 2007; Wong et al, 2006).”
Background
Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington's disease
Giralt, A., Saavedra, A., Carretón, O., Xifró, X., Alberch, J., & Pérez‐Navarro, E. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr351 · Cited by 113
Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimer's disease mice
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Authors: Gong, B., Vitolo, O. V., Trinchese, F., Liu, S., Shelanski, M., & Arancio, O.
Affiliations: Nathan Kline Institute for Psychiatric Research (US)
Columbia University (US)
ORCID: Gong, Bing
Vitolo, Ottavio V.
Trinchese, Fabrizio
Liu, Shumin
Shelanski, Michael
Arancio, Ottavio
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2004-12-01
Volume: 114
Issue: 11
Pages: 1624-1634
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci22831
PMC: PMC529285
OpenAlex: W2034986487
Cited by: 442
References: 60
Citations by year: 2026: 12 · 2025: 14 · 2024: 16 · 2023: 15 · 2022: 11 · 2021: 13 · 2020: 21 · 2019: 20 · 2018: 17 · 2017: 33 · 2016: 17 · 2015: 20 · 2014: 28 · 2013: 23 · 2012: 23
FWCI: 12.13
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Alzheimer's Association
University of Minnesota
York University
National Institutes of Health
School of Medicine, New York University
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, rolipram, amyloid-beta 42, synaptic plasticity, long-term potentiation, contextual learning, memory impairment, phosphodiesterase-4 inhibitors, cAMP/PKA/CREB signaling, synaptic transmission, APP/PS1 double transgenic mice
MeSH terms: Alzheimer Disease, Animals, Cognition, Disease Models, Animal, Hippocampus, Humans, Learning, Male, Membrane Proteins, Mice, Transgenic, Synaptic Transmission, Phosphodiesterase Inhibitors, Amyloid beta-Protein Precursor, Cyclic AMP Response Element-Binding Protein, Long-Term Potentiation, Rolipram, Mice, Presenilin-1, In Vitro Techniques

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Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment

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