Receptor for Advanced Glycation End Product-Dependent Activation of p38 Mitogen-Activated Protein Kinase Contributes to Amyloid-β-Mediated Cortical Synaptic Dysfunction

Abstract

Soluble amyloid-␤ (A␤) peptide is likely to play a key role during early stages of Alzheimer's disease (AD) by perturbing synaptic function and cognitive processes. Receptor for advanced glycation end products (RAGE) has been identified as a receptor involved in A␤-induced neuronal dysfunction. We investigated the role of neuronal RAGE in A␤-induced synaptic dysfunction in the entorhinal cortex, an area of the brain important in memory processes that is affected early in AD. We found that soluble oligomeric A␤ peptide (A␤42) blocked long-term potentiation (LTP), but did not affect long-term depression, paired-pulse facilitation, or basal synaptic transmission. In contrast, A␤ did not inhibit LTP in slices from RAGE-null mutant mice or in slices from wild-type mice treated with anti-RAGE IgG. Similarly, transgenic mice expressing a dominant-negative form of RAGE targeted to neurons showed normal LTP in the presence of A␤, suggesting that neuronal RAGE functions as a signal transducer for A␤-mediated LTP impairment. To investigate intracellular pathway transducing RAGE activation by A␤, we used inhibitors of stress activated kinases. We found that inhibiting p38 mitogen-activated protein kinase (p38 MAPK), but not blocking c-Jun N-terminal kinase activation, was capable of maintaining LTP in A␤-treated slices. Moreover, A␤-mediated enhancement of p38 MAPK phosphorylation in cortical neurons was reduced by blocking antibodies to RAGE. Together, our results indicate that A␤ impairs LTP in the entorhinal cortex through neuronal RAGE-mediated activation of p38 MAPK.

Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

“…These observations agree with the concept that amyloid precursor proteins, not amyloid fibrils, cause organ dysfunction and contribute to the pathophysiology and progression in various amyloid-related diseases (7,8). Among the multiple key mediators involved in the regulation of redox status, stress-responsive p38 mitogen-activated protein kinases (MAPK) have been reported to be activated in other types of amyloid disease such as Alzheimer's disease (9)(10)(11)(12). Our prior findings have implicated oxidative stress in AL-LC-induced cellular dysfunction.…”

RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction

“…However, more recently, it has been appreciated that oligomeric and prefibrillar A␤ and A␤ have similar cytotoxic effects (34) and such soluble forms of A␤ are believed to play a critical role in the pathogenesis of AD. Recent work has demonstrated that oligomeric A␤ , at a concentration of 200 nM, is capable of blocking long-term potentiation at cortical synapses in the hippocampus and entorhinal cortex (10,28,35,36). Taken together, our findings suggest that via RAGE, neuronal transmembrane transport of A␤ and A␤ carries soluble assemblies of amyloid peptide into the cell.…”

“…In addition, Arancio et al (28) reported increased phosphorylation of CREB, ERK1/2, p38 MAPK, and CaMKII in hippocampal extracts from Tg mice overexpressing RAGE and mAPP. RAGE-dependent activation of p38 signal transduction also plays an important role in A␤-mediated synaptic failure (35,36). However, direct links between RAGE-mediated signaling pathways and A␤ neurotoxicity remain to be fully elucidated.…”

Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

“…Finally, given that the inhibition of p38 activation is sufficient to prevent Aβ-induced neurotoxicity, as also observed by others [33,56] , atorvastatin treatment controls AβO-induced neurotoxicity through the regulation of p38MAPK phosphorylation. Activated p38MAPK is observed in human AD brain tissue [57] and in AD-relevant animal models [58,59] , and cell culture studies strongly implicate p38MAPK in the increased production of proinflammatory cytokines in the glia activated by Aβ [60] .…”