Learning deficits and dysfunctional synaptic plasticity induced by aggregated amyloid deposits in the dentate gyrus are rescued by chronic treatment with indomethacin.
The amyloid pathology in Alzheimer's disease is accompanied by a chronic inflammatory response characterized by gliosis and activated microglial cells surrounding senile plaques. Epidemiological studies have shown nonsteroidal anti-inflammatory drug treatment reduces the risk of Alzheimer's disease. We have previously shown that injection of a combination of Abeta40 and Abeta43 in the dentate gyrus of the rat induces aggregated amyloid deposits and inflammation associated with dysfunctional synaptic plasticity and learning deficits. Here we characterize the effectiveness of nonsteroidal anti-inflammatory treatment in this model and show that this treatment restores the working memory deficit and decremental long-term potentiation in the dentate gyrus. Importantly, we observe no qualitative difference in the presence of aggregated material but a substantial reduction in microglial-induced inflammation, suggesting that mature aggregated plaques may not be directly responsible for the deficits but may trigger an inflammatory response which has a detrimental effect on synaptic function and memory.
Stéphan
Aline
A
Laboratoire de Neurobiologie de l'Apprentissage, de la Mémoire et de la Communication, CNRS UMR 8620, Université Paris Sud, Bât 446, 91405 Orsay, France.
Laroche
Serge
S
Davis
Sabrina
S
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects / Q000502:physiology; D018891:Dentate Gyrus / Q000187:drug effects* / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007213:Indomethacin / Q000008:administration & dosage*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C098994:amyloid beta-protein (1-43); D007213:Indomethacin