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

PM Canas, LO Porciúncula, GMA Cunha… - Journal of …, 2009 - Soc Neuroscience
PM Canas, LO Porciúncula, GMA Cunha, CG Silva, NJ Machado, JMA Oliveira, CR Oliveira…
Journal of Neuroscience, 2009Soc Neuroscience
Alzheimer's disease (AD) is characterized by memory impairment, neurochemically by
accumulation of β-amyloid peptide (namely Aβ1-42) and morphologically by an initial loss of
nerve terminals. Caffeine consumption prevents memory dysfunction in different models,
which is mimicked by antagonists of adenosine A2A receptors (A2ARs), which are located in
synapses. Thus, we now tested whether A2AR blockade prevents the early Aβ1-42-induced
synaptotoxicity and memory dysfunction and what are the underlying signaling pathways …
Alzheimer's disease (AD) is characterized by memory impairment, neurochemically by accumulation of β-amyloid peptide (namely Aβ1-42) and morphologically by an initial loss of nerve terminals. Caffeine consumption prevents memory dysfunction in different models, which is mimicked by antagonists of adenosine A2A receptors (A2ARs), which are located in synapses. Thus, we now tested whether A2AR blockade prevents the early Aβ1-42-induced synaptotoxicity and memory dysfunction and what are the underlying signaling pathways. The intracerebral administration of soluble Aβ1-42 (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 A2ARs in mice. Moreover, these were synaptic events since purified nerve terminals acutely exposed to Aβ1-42 (500 nm) displayed mitochondrial dysfunction, which was prevented by A2AR 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 Aβ1-42 (500 nm). This A2AR-mediated control of neurotoxicity involved the control of Aβ1-42-induced p38 phosphorylation and was independent from cAMP/PKA (protein kinase A) pathway. Together, these results show that A2ARs 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.
Soc Neuroscience