Beta-amyloid(1-42) induces a reduction in the parallel fiber responses of Purkinje cells: possible involvement of pro-inflammatory processes.
In Alzheimer's disease there is an increased production of the toxic beta-amyloid peptides (Abeta), especially the longer forms such as Abeta(1-42). Using the patch-clamp technique we have studied the contribution of early pro-inflammatory processes to the acute effects of 1 microM Abeta(1-42) on the parallel fiber EPSC (PF-EPSC) of Purkinje cells in cerebellar slices. Abeta(1-42) induces a decrease in the PF-EPSC amplitude. This decrease is accompanied by a decrease in the frequency and amplitude of the miniature EPSCs, suggesting that Abeta acts at both pre- and post-synaptic sites. In the presence of L-NAME, a nitric oxide synthase inhibitor, the effects of Abeta were partially blocked. The frequency of mEPSCs was unchanged while Abeta still reduced the mEPSCs amplitude. The anti-inflammatory agent flurbiprofen blocked the depressant action of Abeta on the mEPSCs amplitude but not its effect on mEPSCs frequency. Both a p38 inhibitor (SB203580) and a JNK inhibitor (SP600125) reverse the effects of Abeta as an increase in the mEPSCs frequency and amplitude was observed. This study provides evidence that the Abeta-induced depression of the PF-EPSCs was mediated via an activation of JNK and p38 and by the action of NO and raises the possibility of the involvement of an early pro-inflammatory process.
Arbez
Nicolas
N
Equipe Développement et Vieillissement du Système Nerveux, UMR 7102, UPMC-CNRS, Lab DVSN, 9, Quai St Bernard, Case 14, Paris F-75005, France.
Gautheron
Vanessa
V
Brugg
Bernard
B
Mariani
Jean
J
Rovira
Catherine
C
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005480:Flurbiprofen / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011689:Purkinje Cells / Q000187:drug effects* / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; C579166:Chrna7 protein, mouse; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid; D005480:Flurbiprofen; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester