The DOI matches its Crossref record; 78 of the 78 references it cites were found in a registry or an index.
Adenosine A2AReceptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by β-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway
Open accessAbstract
Alzheimer's disease (AD) is characterized by memory impairment, neurochemically by accumulation of β-amyloid peptide (namely Aβ 1-42) and morphologically by an initial loss of nerve terminals. Caffeine consumption prevents memory dysfunction in different models, which is mimicked by antagonists of adenosine A 2A receptors (A 2A Rs), which are located in synapses. Thus, we now tested whether A 2A R blockade prevents the early Aβ 1-42-induced synaptotoxicity and memory dysfunction and what are the underlying signaling pathways. The intracerebral administration of soluble Aβ 1-42(2 nmol) in rats or mice caused, 2 weeks later, memory impairment (decreased performance in the Y-maze and object recognition tests) and a loss of nerve terminal markers (synaptophysin, SNAP-25) without overt neuronal loss, astrogliosis, or microgliosis. These were prevented by pharmacological blockade [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261); 0.05 mg · kg−1· d−1, i.p.; for 15 d] in rats, and genetic inactivation of A 2A Rs in mice. Moreover, these were synaptic events since purified nerve terminals acutely exposed to Aβ 1-42(500 n m) displayed mitochondrial dysfunction, which was prevented by A 2A R blockade. SCH58261 (50 n m) also prevented the initial synaptotoxicity (loss of MAP-2, synaptophysin, and SNAP-25 immunoreactivity) and subsequent loss of viability of cultured hippocampal neurons exposed to Aβ 1-42(500 n m). This A 2A R-mediated control of neurotoxicity involved the control of Aβ 1-42-induced p38 phosphorylation and was independent from cAMP/PKA (protein kinase A) pathway. Together, these results show that A 2A Rs play a crucial role in the development of Aβ-induced synaptotoxicity leading to memory dysfunction through a p38 MAPK (mitogen-activated protein kinase)-dependent pathway and provide a molecular basis for the benefits of caffeine consumption in AD.
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Cites
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Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models
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Cited by
Adenosine receptors and brain diseases: neuroprotection and neurodegeneration
Gomes, C. V., Kaster, M. P., Tomé, A. R., Agostinho, P. M., & Cunha, R. A. (2011) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2010.12.001 · Cited by 419
Self-citationKaster, M. P., Machado, N. J., Silva, H. B., Nunes, A., Ardais, A. P., Santana, M., Baqi, Y., Müller, C. E., Rodrigues, A. L. S., Porciúncula, L. O., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1423088112 · Cited by 312
Self-citationThe role of G protein-coupled receptors in the pathology of Alzheimer's disease
Thathiah, A., & De Strooper, B. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn2977 · Cited by 288
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Adenosine receptor antagonists including caffeine alter fetal brain development in mice
Silva, C. G., Métin, C., Fazeli, W., Machado, N. J., Darmopil, S., Launay, P.-S., Ghestem, A., Nesa, M.-P., Bassot, E., Szabó, E., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006258 · Cited by 177
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Metadata
- Authors
- Canas, P. M., Porciúncula, L. O., Cunha, G. M. A., Silva, C. G., Machado, N. J., Oliveira, J. M. A., Oliveira, C. R., & Cunha, R. A.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-11-25
- Volume
- 29
- Issue
- 47
- Pages
- 14741-14751
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- OpenAlex
- W2130302474
- Cited by
- 357
- References
- 78
- FWCI
- 9.25
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Canas, P. M., Porciúncula, L. O., Cunha, G. M. A., Silva, C. G., Machado, N. J., Oliveira, J. M. A., Oliveira, C. R., & Cunha, R. A. (2009). Adenosine A2AReceptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by β-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway. The Journal of Neuroscience. https://doi.org/10.1523/jneurosci.3728-09.2009
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