Overproduction of beta-amyloid (A beta) is a pathologic feature of Alzheimer's disease, leading to cognitive impairment. Here, we investigated the impact of cell-specific receptor for advanced glycation end products (RAGE) on A beta-induced entorhinal cortex (EC) synaptic dysfunction. We found both a transient depression of basal synaptic transmission and inhibition of long-term depression (LTD) after the application of A beta in EC slices. Synaptic depression and LTD impairment induced by A beta were rescued by functional suppression of RAGE. Remarkably, the rescue was only observed in slices from mice expressing a defective form of RAGE targeted to microglia, but not in slices from mice expressing defective RAGE targeted to neurons. Moreover, we found that the inflammatory cytokine IL-1 beta (interleukin-1 beta) and stress-activated kinases [p38 MAPK (p38 mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase)] were significantly altered and involved in RAGE signaling pathways depending on RAGE expression in neuron or microglia. These findings suggest a prominent role of microglial RAGE signaling in A beta-induced EC synaptic dysfunction.

Microglial Receptor for Advanced Glycation End Product-Dependent Signal Pathway Drives beta-Amyloid-Induced Synaptic Depression and Long-Term Depression Impairment in Entorhinal Cortex

DOMENICI, LUCIANO
2010-01-01

Abstract

Overproduction of beta-amyloid (A beta) is a pathologic feature of Alzheimer's disease, leading to cognitive impairment. Here, we investigated the impact of cell-specific receptor for advanced glycation end products (RAGE) on A beta-induced entorhinal cortex (EC) synaptic dysfunction. We found both a transient depression of basal synaptic transmission and inhibition of long-term depression (LTD) after the application of A beta in EC slices. Synaptic depression and LTD impairment induced by A beta were rescued by functional suppression of RAGE. Remarkably, the rescue was only observed in slices from mice expressing a defective form of RAGE targeted to microglia, but not in slices from mice expressing defective RAGE targeted to neurons. Moreover, we found that the inflammatory cytokine IL-1 beta (interleukin-1 beta) and stress-activated kinases [p38 MAPK (p38 mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase)] were significantly altered and involved in RAGE signaling pathways depending on RAGE expression in neuron or microglia. These findings suggest a prominent role of microglial RAGE signaling in A beta-induced EC synaptic dysfunction.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11697/18556
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