Inhibition of LTP by beta-amyloid is prevented by activation of beta2 adrenoceptors and stimulation of the cAMP/PKA signalling pathway.
Beta-amyloid (Abeta) is the main component of the extracellular plaques present in patients with Alzheimer's disease (AD) and studies have shown that exogenous application of Abeta results in neurodegeneration. As a model of the neurodegenerative action of Abeta, we have previously shown that acutely applied Abeta inhibits the induction of LTP in the hippocampus in vitro. In the present studies, we have studied the effect of beta-adrenoceptor activation on the Abeta inhibition of LTP. Pharmacological activation of beta2 adrenoceptors, but not of beta1 adrenoceptors, was found to prevent the Abeta evoked inhibition of LTP in the dentate gyrus of adult animals. The prevention of the effect of Abeta was shown to occur via the cAMP/PKA signaling pathway as the adenylate cyclase-stimulating agent forskolin prevented the Abeta inhibition of LTP, an action prevented by the PKA inhibitor, Rp-8-Br-cAMPs. We suggest microglia as a likely site of action of the neuroprotective effect of beta2 adrenoceptor activation. Therapeutic treatment for AD may include agents that activate beta2 receptors and elevate cAMP.
Wang
Qin-Wen
QW
Department of Physiology, Trinity College, Dublin 2, Ireland.
Rowan
Michael J
MJ
Anwyl
Roger
R
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D018663:Adrenergic Agents / Q000494:pharmacology; D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology*; D004280:Dobutamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013726:Terbutaline / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology
C105593:8-bromoadenosine-3',5'-cyclic monophosphorothioate; D018663:Adrenergic Agents; D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D013873:Thionucleotides; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004280:Dobutamine; C026777:ICI 118551; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D013726:Terbutaline