Adenosine A(2A) Receptor Blockade Prevents Synaptotoxicity and Memory Dysfunction Caused by beta-Amyloid Peptides via p38 Mitogen-Activated Protein Kinase Pathway

• Type: Article in International Scientific Journal
• Date: 2009

Authors

Paula M Canas (Author) Other; Lisiane O Porciuncula (Author) Other; Geanne M A Cunha (Author) Other; Carla G Silva (Author) Other; Nuno J Machado (Author) Other; Jorge M A Oliveira (Author) FFUP; Catarina R Oliveira (Author) Other; Rodrigo A Cunha (Author) Other

Journal

Title: Journal of Neuroscience

Vol. 29

Pages: 14741-14751

ISSN: 0270-6474

Publisher: Society for Neuroscience

Indexing

ISI Web of Knowledge - 174 Citations

ISI Web of Science

Scopus - 239 Citations

Pubmed / Medline

Scientific classification

FOS: Medical and Health sciences > Basic medicine

CORDIS: Health sciences > Neuroscience ; Health sciences > Pharmacological sciences

Other information

Authenticus ID: P-003-EA1

DOI: 10.1523/jneurosci.3728-09.2009

Resumo (PT): 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. <br> <br> <a target="_blank" href="http://www.jneurosci.org/cgi/content/abstract/29/47/14741"> Texto integral</a> <br> <br>

Abstract (EN): Alzheimer's disease (AD) is characterized by memory impairment, neurochemically by accumulation of beta-amyloid peptide (namely A beta(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 A beta(1-42)-induced synaptotoxicity and memory dysfunction and what are the underlying signaling pathways. The intracerebral administration of soluble A beta(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 A beta(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 A beta(1-42) (500 nM). This A(2A)R-mediated control of neurotoxicity involved the control of A beta(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 A beta-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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11