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Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway.

ABSTRACT: Alzheimer's disease (AD) is characterized by memory impairment, neurochemically by accumulation of beta-amyloid peptide (namely Abeta(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 Abeta(1-42)-induced synaptotoxicity and memory dysfunction and what are the underlying signaling pathways. The intracerebral administration of soluble Abeta(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 Abeta(1-42) (500 nm) displayed mitochondrial dysfunction, which was prevented by A(2A)R blockade. SCH58261 (50 nm) 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 Abeta(1-42) (500 nm). This A(2A)R-mediated control of neurotoxicity involved the control of Abeta(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 Abeta-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.

SUBMITTER: Canas PM

PROVIDER: S-EPMC6665997 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway.

Canas Paula M PM Porciúncula Lisiane O LO Cunha Geanne M A GM Silva Carla G CG Machado Nuno J NJ Oliveira Jorge M A JM Oliveira Catarina R CR Cunha Rodrigo A RA

The Journal of neuroscience : the official journal of the Society for Neuroscience 20091101 47

Alzheimer's disease (AD) is characterized by memory impairment, neurochemically by accumulation of beta-amyloid peptide (namely Abeta(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 Abeta(1-42)-induced synaptotoxicity and memory dysfunction and ...[more]

PMID: 19940169

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Project description:BACKGROUND AND PURPOSE: Blockade of adenosine A(2A) receptors (A(2A)R) affords robust neuroprotection in a number of brain conditions, although the mechanisms are still unknown. A likely candidate mechanism for this neuroprotection is the control of neuroinflammation, which contributes to the amplification of neurodegeneration, mainly through the abnormal release of pro-inflammatory cytokines such as interleukin(IL)-1?. We investigated whether A(2A)R controls the signaling of IL-1? and its deleterious effects in cultured hippocampal neurons. METHODS: Hippocampal neuronal cultures were treated with IL-1? and/or glutamate in the presence or absence of the selective A(2A)R antagonist, SCH58261 (50 nmol/l). The effect of SCH58261 on the IL-1?-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) c-Jun N-terminal kinase (JNK) and p38 was evaluated by western blotting and immunocytochemistry. The effect of SCH58261 on glutamate-induced neurodegeneration in the presence or absence of IL-1? was evaluated by nucleic acid and by propidium iodide staining, and by lactate dehydrogenase assay. Finally, the effect of A(2A)R blockade on glutamate-induced intracellular calcium, in the presence or absence of IL-1?, was studied using single-cell calcium imaging. RESULTS: IL-1? (10 to 100 ng/ml) enhanced both JNK and p38 phosphorylation, and these effects were prevented by the IL-1 type 1 receptor antagonist IL-1Ra (5 ?g/ml), in accordance with the neuronal localization of IL-1 type 1 receptors, including pre-synaptically and post-synaptically. At 100 ng/ml, IL-1? failed to affect neuronal viability but exacerbated the neurotoxicity induced by treatment with 100 ?mol/l glutamate for 25 minutes (evaluated after 24 hours). It is likely that this resulted from the ability of IL-1? to enhance glutamate-induced calcium entry and late calcium deregulation, both of which were unaffected by IL-1? alone. The selective A(2A)R antagonist, SCH58261 (50 nmol/l), prevented both the IL-1?-induced phosphorylation of JNK and p38, as well as the IL-1?-induced deregulation of calcium and the consequent enhanced neurotoxicity, whereas it had no effect on glutamate actions. CONCLUSIONS: These results prompt the hypothesis that the neuroprotection afforded by A(2A)R blockade might result from this particular ability of A(2A)R to control IL-1?-induced exacerbation of excitotoxic neuronal damage, through the control of MAPK activation and late calcium deregulation.

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Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway.

Publications

Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway.

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