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Published on: January 28, 2019
Microglial receptor for advanced glycation end product-dependent signal pathway drives beta-amyloid-induced synaptic
Nicola Origlia1, Camilla Bonadonna, Alfredo Rosellini
1Neuroscience Institute, Italian National Research Council, Pisa, 56100 Pisa, Italy.
Abstract:
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.
Insights
Microglial receptor for advanced glycation end products (RAGE) significantly impacts Alzheimer's disease pathology. Suppressing microglial RAGE, not neuronal RAGE, rescues beta-amyloid-induced synaptic dysfunction in the entorhinal cortex.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Alzheimer's disease (AD) is characterized by beta-amyloid (Abeta) overproduction, leading to cognitive decline.
- The receptor for advanced glycation end products (RAGE) is implicated in AD pathogenesis.
- Cell-specific roles of RAGE in Abeta-induced synaptic dysfunction remain unclear.
Purpose of the Study:
- To investigate the impact of cell-specific RAGE on Abeta-induced synaptic dysfunction in the entorhinal cortex (EC).
- To elucidate the signaling pathways involving RAGE in this context.
Main Methods:
- Application of Abeta to mouse EC slices.
- Functional suppression of RAGE in microglia and neurons.
- Electrophysiological recordings to assess synaptic transmission and long-term depression (LTD).
- Analysis of inflammatory cytokines (IL-1beta) and stress-activated kinases (p38 MAPK, JNK).
Main Results:
- Abeta application induced synaptic depression and impaired LTD in EC slices.
- Functional suppression of RAGE rescued Abeta-induced synaptic dysfunction.
- This rescue was specific to RAGE suppression in microglia, not neurons.
- Microglial RAGE signaling involved altered IL-1beta and stress-activated kinase pathways.
Conclusions:
- Microglial RAGE plays a critical role in Abeta-induced EC synaptic dysfunction.
- Targeting microglial RAGE may offer a therapeutic strategy for Alzheimer's disease.
- RAGE signaling in microglia influences inflammatory and stress pathways relevant to AD.
