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

Abstract

Overproduction of ␤-amyloid (A␤) 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␤-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␤ in EC slices. Synaptic depression and LTD impairment induced by A␤ 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␤ (interleukin-1␤) 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␤-induced EC synaptic dysfunction.

RAGE: The Beneficial and Deleterious Effects by Diverse Mechanisms of Actions

“…Nevertheless, oligomeric Aβ, extracted directly from the cerebral cortex of AD patients, inhibits LTP, enhances LTD, reduces dendritic spine density, and impairs the memory of learned behavior in normal rodents (Shankar et al, 2008). Recent study by Origlia et al proposes that the pivotal role of microglial RAGE to regulates Aβ-induced synaptic depression and LTD impairment (Origlia et al, 2010).…”

“…Neuronal RAGE binds to Aβ and upregulates RAGE expression followed by more Aβ generation, causing neuronal toxicity and synaptic dysfunction (Arancio et al, 2004;Cho et al, 2009;Origlia et al, 2008;Yan et al, 1996). RAGE also mediates Aβ-induced microglial proliferation and migration and stimulates and amplifies inflammatory responses -distinct hallmarks of AD (Bianchi et al, 2010;Fang et al, 2010;Origlia et al, 2010). RAGE in the blood brain barrier (BBB) is the primary means by which Aβ enters the brain compartment (Deane and Zlokovic, 2007;Mackic et al, 1998;Yan et al, 1996).…”

Synaptic Function and Dysfunction in Alzheimer’s Disease

“…In particular, low level of synthetic oligomeric Aβ42 inhibits LTP in hippocampus and entorhinal cortex through phosphorylation of p38 MAPK in neurons [45,57,58]. Increasing Aβ induces specific phosphorylation of p38 MAPK and JNK in neuronal and non-neuronal cells along with the induction of pro-inflammatory cytokines, such as the IL-β; as above reported in this condition basal synaptic transmission and long-term synaptic plasticity are affected [51].…”

“…This might be the consequence of a particular vulnerability of the superficial layer II neurons, that are susceptible to the deleterious consequences of aging and AD [50]. Interestingly, increasing synthetic Aβ42 concentration induces activation of microglial cells with pro-inflammatory cytokines that progressively affects synaptic transmission, AMPA current and long term depression (LTD, a second form of long term synaptic plasticity), in addition to LTP [51]. Indeed, an increasing level of Aβ42 has been shown to induce synaptic transmission impairment by regulating glutamate receptors trafficking [52,53].…”

“…Thus, progression of synaptic dysfunction as well as cognitive decline by accumulation of extracellular Aβ is likely to result in alterations of pre-and post-synaptic proteins [55]. Activation of receptors such as the receptor for advanced glycation end products (RAGE) by Aβ [56] accounts for progress of synaptic dysfunction, development of inflammatory and, possibly, oxidative processes, leading cells to degenerate [51]. Concerning the receptor signaling pathways mediating synaptic dysfunction, it has been reported that Aβ impairs LTP in the hippocampus through JNK, cyclin-dependent The APP processing.…”