Microglial receptor for advanced glycation end product-dependent signal pathway drives beta-amyloid-induced synaptic depression and long-term depression impairment in entorhinal cortex.
Overproduction of beta-amyloid (Abeta) 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 Abeta-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 Abeta in EC slices. Synaptic depression and LTD impairment induced by Abeta 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-1beta (interleukin-1beta) 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 Abeta-induced EC synaptic dysfunction.
Origlia
Nicola
N
Neuroscience Institute, Italian National Research Council, Pisa, 56100 Pisa, Italy.
Bonadonna
Camilla
C
Rosellini
Alfredo
A
Leznik
Elena
E
Arancio
Ottavio
O
Yan
Shirley Shidu
SS
Domenici
Luciano
L
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D018728:Entorhinal Cortex / Q000378:metabolism / Q000503:physiopathology*; D017127:Glycation End Products, Advanced / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D016229:Amyloid beta-Peptides; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic