Brain-derived neurotrophic factor mediates neuroprotection against Aß-induced toxicity through a mechanism independent on adenosine 2A receptor activation.

Brain-derived neurotrophic factor (BDNF) promotes neuronal survival through TrkB-FL activation. The activation of adenosine A2A receptors (A2AR) is essential for most of BDNF-mediated synaptic actions, such as synaptic plasticity, transmission and neurotransmitter release. We now aimed at evaluating the A2AR influence upon BDNF-mediated neuroprotection against Aß25-35 toxicity in cultured neurons. Results showed that BDNF increases cell survival and reduces the caspase-3 and calpain activation induced by amyloid-ß (Aß) peptide, in a mechanism probably dependent on PLCγ pathway. This BDNF-mediated neuroprotection is not affected by A2AR activation or inhibition. Moreover neither activation nor inhibition of A2AR, per se, significantly influenced Aß-induced neuronal death on calpain-mediated cleavage of TrkB induced by Aß. In conclusion, these results suggest that, in opposition to the fast synaptic actions of BDNF, the neuroprotective actions of this neurotrophin against a strong Aß insult do not require the activation of A2AR.

Impact of in vivo chronic blockade of adenosine A2A receptors on the BDNF-mediated facilitation of LTP.

Brain-derived neurotrophic factor (BDNF) through the activation of its receptor (TrkB-FL) exert well-described neuroprotective effects playing a major role in hippocampal synaptic transmission and plasticity such as long-term potentiation (LTP), a molecular surrogate for learning and memory. Impairments in BDNF signalling have been associated to several neurodegenerative disorders such as Alzheimer's disease (AD). Therefore, the reestablishment of BDNF actions is considered a promising strategy for AD treatment. While, most of BDNF synaptic actions, namely on LTP, require the activation of adenosine A2A receptor (A2AR), the antagonists of A2AR have been proven to prevent AD induced deficits in different animal models. Therefore in this work we aimed to evaluate the impact of a chronic in vivo oral administration of an A2AR antagonist (KW-6002) in the BDNF actions upon hippocampal CA1 LTP. The results showed that chronic blockade of A2AR in male Wistar rats inhibits the facilitatory action of BDNF upon LTP on hippocampal CA1 area and decreases both mRNA and protein levels of the TrkB-FL receptor in hippocampus. These findings imply that BDNF signalling may be affected in chronic A2AR blocking conditions.

Adenosine A(2A) Receptors as novel upstream regulators of BDNF-mediated attenuation of hippocampal Long-Term Depression (LTD).

Hippocampal Long-Term Potentiation (LTP) is facilitated by BDNF, through the activation of tropomyosin-related kinase B (TrkB) receptors. However, an influence of BDNF upon Long-Term Depression (LTD) was also shown. The present work aimed to further evaluate the effect of BDNF and TrkB receptors upon CA1 hippocampal LTD and to elucidate whether this effect is under the upstream control of other signalling processes, such as the adenosine A(2A)Receptors (A(2A)Rs). LTD, induced by a Low-Frequency Stimulation (LFS, 900 pulses, 1 Hz) in the CA1 area of rat hippocampal slices, was significantly attenuated when these slices were exposed to BDNF (60-100 ng/mL). A lower BDNF concentration (20 ng/ml) was only effective to inhibit LTD if A(2A)Rs were activated by a selective agonist, CGS 21680 (10 nM), or if the extracellular adenosine level was increased by 5-iodotubercidin (100 nM). BDNF (100 ng/ml) effect upon LTD was prevented by K252a (200 nM), which is known to prevent TrkB transphosphorylation, hence suggesting that this action requires TrkB receptor activation. BDNF (100 ng/ml) lacked effect on an adenosine-depleted background (adenosine deaminase, 2 U/ml) or under selective A(2A)R blockade (SCH 58261, 100 nM), indicating that it relies on tonic A(2A)R activation. Forskolin (10 µM), a cell-permeable activator of adenylate cyclase, rescued BDNF (100 ng/ml) effect in slices where A(2A)Rs were blocked with SCH 58261 (100 nM), whereas a PKA inhibitor, H-89 (1 µM), prevented LTD attenuation by BDNF (100 ng/ml). We conclude that the influence of BDNF TrkB receptors upon LTD is under the strict control of A(2A)Rs activation, through a mechanism that requires the cAMP/PKA transducing system.

Enhancement of LTP in aged rats is dependent on endogenous BDNF.

Long-term potentiation (LTP), considered the neurophysiological basis for learning and memory, is facilitated by brain-derived neurotrophic factor (BDNF), an action more evident when LTP is evoked by weak θ-burst stimuli and dependent on co-activation of adenosine A(2A) receptors (A(2A)R), which are more expressed in aged rats. As θ-burst stimuli also favor LTP in aged animals, we hypothesized that enhanced LTP in aging could be related to changes in neuromodulation by BDNF. The magnitude of CA1 LTP induced by a weak θ-burst stimuli delivered to the Schaffer collaterals was significantly higher in hippocampal slices taken from 36 to 38 and from 70 to 80-week-old rats, when compared with LTP magnitude in slices from 4 or 10 to 15-week-old rats; this enhancement does not impact in cognitive improvement as aged rats revealed an impairment on hippocampal-dependent learning and memory performance, as assessed by the Morris water maze tests. The scavenger for BDNF, TrkB-Fc, and the inhibitor of Trk phosphorylation, K252a, attenuated LTP in slices from 70 to 80-week-old rats, but not from 10 to 15-week-old rats. When exogenously added, BDNF significantly increased LTP in slices from 4 and 10 to 15-week-old rats, but did not further increased LTP in 36 to 38 or 70 to 80-week-old rats. The effects of exogenous BDNF on LTP were prevented by the A(2A)R antagonist, SCH58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine). These results indicate that the higher LTP magnitude observed upon aging, which does not translate into improved spatial memory performance, is a consequence of an increase in the tonic action of endogenous BDNF.