The DOI matches its Crossref record; 74 of the 75 references it cites were found in a registry or an index.
Phosphodiesterase-4 (PDE4) Molecular Pharmacology and Alzheimer's Disease
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The APP/PS1 mouse model of AD develops long-term potentiation (LTP) deficits, but rolipram-treated APP/PS1 mice showed comparable LTP induction to wild-type animals85.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [85]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Glenner, G. G., & Wong, C. W. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(84)80190-4 · Cited by 5,404
Goate, A., Chartier-Harlin, M.-C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., et al. (1991) · Nature · doi:10.1038/349704a0 · Cited by 4,659
Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B
Klunk, W. E., Engler, H., Nordberg, A., Wang, Y., Blomqvist, G., Holt, D. P., Bergström, M., Savitcheva, I., Huang, G., Estrada, S., et al. (2004) · Annals of Neurology · doi:10.1002/ana.20009 · Cited by 4,496
Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., et al. (1995) · Nature · doi:10.1038/375754a0 · Cited by 4,051
Hearing loss and cognitive decline in older adults
Lin, F. R., Yaffe, K., Xia, J., Xue, Q.-L., Harris, T. B., Purchase-Helzner, E., Satterfield, S., Ayonayon, H. N., Ferrucci, L., Simonsick, E. M., et al. (2013) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2013.1868 · Cited by 4,017
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876
Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., et al. (1996) · Nature Medicine · doi:10.1038/nm0896-864 · Cited by 2,599
Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease
Salloway, S., Sperling, R., Fox, N. C., Blennow, K., Klunk, W., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., Ferris, S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1304839 · Cited by 1,960
A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline
Jonsson, T., Atwal, J. K., Steinberg, S., Snaedal, J., Jonsson, P. V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., et al. (2012) · Nature · doi:10.1038/nature11283 · Cited by 1,738
Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease
Doody, R. S., Thomas, R. G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., Raman, R., Sun, X., Aisen, P. S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1312889 · Cited by 1,668
Flagged first, then by citations
1 of the 75 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- Gong, 2004, Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment, J Clin Invest, 114, 1624, 10.1172/JCI22831 · DOI · Paper page
- Li, 2011, Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling, J Neurosci, 31, 172, 10.1523/JNEUROSCI.5236-10.2011 · DOI
Cited by
Sorted by citations
Items 101–127 of 127
Chen, J., Xiao, S., Cui, X., Gao, X. P., Wang, D., Li, X., Qi, W., & Wang, B. (2025) · Metabolic Brain Disease · doi:10.1007/s11011-025-01652-4 · Cited by 3
Targeting Phosphodiesterases in the CNS
Kehler, J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-409547-2.12445-x · Cited by 2
Phosphodiesterase 4 inhibition as a novel treatment for stroke
Zhong, J., Yu, X.-H., & Lin, Z. (2025) · PeerJ · doi:10.7717/peerj.18905 · Cited by 1
Zhao, W., Wang, Z., Chen, X., Zhao, S., Zong, F., & Zhang, H. (2025) · The FASEB Journal · doi:10.1096/fj.202501537r · Cited by 1
Phosphodiesterase: insight from molecular targets for glycolipid metabolism
Dang, L., Liang, C., Han, Q., & Sun, C. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.153188 · Cited by 1
Alzheimer's disease therapeutics
Sang, Z., & Huang, L. (2023) · Elsevier eBooks · doi:10.1016/b978-0-443-18611-0.00031-0 · Cited by 1
Zhao, H., Blokland, A., Prickaerts, J., Havekes, R., Meijer, E. L., & Heckman, P. R. A. (2025) · Learning & Memory · doi:10.1101/lm.054101.125 · Cited by 1
Enhanced cGMP-dependent signaling in astrocytes: Novel therapeutic target for Alzheimer’s Disease
Woart, N., Winkler, J., Ma, H., & White, R. E. (2015) · Digital Commons - PCOM (Philadelphia College of Osteopathic Medicine)
Schepers, M. (2023) · Research Publications (Maastricht University) · doi:10.26481/dis.20230522ms
Paes, D. (2023) · Research Publications (Maastricht University) · doi:10.26481/dis.20231117dp
Bittmann, S. (2024) · Asian Journal of Pediatric Research · doi:10.9734/ajpr/2024/v14i7359
Phosphodiesterase 4 as a therapeutic target in Parkinson's disease recent advances
Zhong, J., Xu, J., Xue, J., Qiu, Z., Chen, B., Yu, X., & Lin, Z. (2026) · Experimental Neurology · doi:10.1016/j.expneurol.2026.115680
Joshi, A., Mitra, B., Sudesh, R., Arumugam, M., Balakrishnan, B., Haque, S., Lage, M. Á. P., & Ahmad, F. (2026) · Acta Neurologica Scandinavica · doi:10.1155/ane/7255903
Fu, T., Shi, Y., Yang, Z., Zhou, J., Huang, L., Fu, Y., & Xiong, W. (2026) · Biomolecules · doi:10.3390/biom16040570
Pyrazolo[3,4-b]pyridine: a privileged scaffold for the synthesis of anti-Alzheimer’s agents
Waly, O. M., El‐Sayed, S. M., Ghaly, M. A., & El‐Subbagh, H. I. (2026) · Future Journal of Pharmaceutical Sciences · doi:10.1186/s43094-026-01006-6
Blednov, Y. A., Mason, S., Mayfield, J., Sriramoji, S., Bocarsly, M. E., & Messing, R. O. (2026) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/j.jpet.2026.105040
BindingDB (2023) · UC San Diego · doi:10.7270/q2fb56xk
BindingDB Entry 50012720: Advances in the Development of Phosphodiesterase-4 Inhibitors.
BindingDB (2022) · UC San Diego · doi:10.7270/q2w95dvv
BindingDB Entry 50020765: Advances in the development of phosphodiesterase-4 inhibitors.
BindingDB (2024) · UC San Diego · doi:10.7270/q2g44vr2
Metadata
- Authors
- Gurney, M. E., D'Amato, E. C., & Burgin, A. B.
- Affiliations
- Tetra Therapeutics (United States) (US)
- Broad Institute (US)
- Corresponding author
- Gurney, Mark E.
- Venue
- Neurotherapeutics
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 12
- Issue
- 1
- Pages
- 49-56
- ISSN
- 1878-7479 (ISSN-L)
- PMC
- PMC4322084
- OpenAlex
- W2078329648
- Cited by
- 121
- References
- 75
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 14 · 2023: 11 · 2022: 6 · 2021: 6 · 2020: 12 · 2019: 11 · 2018: 12 · 2017: 16 · 2016: 8 · 2015: 6
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neurotherapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R44MH091791, R43MH091791)
- National Institute of Neurological Disorders and Stroke (U01NS078034)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- phosphodiesterase 4, Alzheimer's disease, negative allosteric modulators, PDE4B, PDE4D, cAMP signaling, CREB, neuroinflammation, acrodysostosis, intellectual disability, memory consolidation
- MeSH terms
- Alzheimer Disease, Animals, Humans, Cyclic Nucleotide Phosphodiesterases, Type 4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
