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

• Published in: The Journal of neuroscience 2009-11, Vol.29 (47), p.14741-14751
• Main Authors: Canas, Paula M., Porciúncula, Lisiane O., Cunha, Geanne M. A., Silva, Carla G., Machado, Nuno J., Oliveira, Jorge M. A., Oliveira, Catarina R., Cunha, Rodrigo A.
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3728-09.2009

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.