Involvement of p38 MAPK in Synaptic Function and Dysfunction

Abstract

Many studies have revealed a central role of p38 MAPK in neuronal plasticity and the regulation of long-term changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). However, p38 MAPK is classically known as a responsive element to stress stimuli, including neuroinflammation. Specific to the pathophysiology of Alzheimer's disease (AD), several studies have shown that the p38 MAPK cascade is activated either in response to the Aβ peptide or in the presence of tauopathies. Here, we describe the role of p38 MAPK in the regulation of synaptic plasticity and its implication in an animal model of neurodegeneration. In particular, recent evidence suggests the p38 MAPK α isoform as a potential neurotherapeutic target, and specific inhibitors have been developed and have proven to be effective in ameliorating synaptic and memory deficits in AD mouse models.

Keywords: Alzheimer’s disease; Tau; neuroinflammation; p38-MAPK α inhibitor; synaptic plasticity; β-amyloid.

Figure 1

Overview of the p38 mitogen activated protein kinase (MAPK) signal transduction pathways in neurons, astrocytes, and microglia. p38 MAPK can be activated in response to various extracellular stimuli, such as glutamate, advanced glycation endproducts (AGEs), cytokines, and chemokines, leading to cell type-specific downstream effects. (a) In neuronal cells, the activation of the metabotropic glutamate receptors of group I (group I mGluRs) can turn on phospholipase C (PLC) and promote the phosphorylation of MAP kinase kinase 3/6 (MKK 3/6), with the subsequent activation of the p38 MAPKs. The α and β isoforms of p38 MAPK have been shown to inhibit beta-secretase 1 degradation, to promote the activation of MAP kinase activated protein kinase (MAPKAKP), and to act on specific transcription factors (TFs) to induce changes in the expression of the key proteins involved in synaptic plasticity, such as the fragile X mental retardation protein (FMRP), the activity-regulated cytoskeleton-associated protein (Arc), the c-fos protein, and the brain-derived neurotrophic factor (BDNF). On the other hand, the γ and δ isoforms seem to have a role in the modulation of synaptic proteins, such as postsynaptic density protein 95 (PSD95) and the microtubule-associated protein Tau. Furthermore, AGEs binding to the receptor for advanced glycation endproducts (RAGE) can turn on the Ras protein, and predominantly lead to the activation of p38 α and β isoforms, while cytokines and chemokines can trigger p38 MAPK by acting through their specific receptors and via MKKs. (b) In astrocytes, AGEs and pro-inflammatory molecules such as lipopolysaccharide (LPS) can lead to p38 MAPK activation as well. Moreover, p38 activation in this specific cell type has been demonstrated to modulate hippocampal n-methyl-d-aspartate (NMDA)-dependent long-term depression (LTD), to induce the production of the S100 calcium binding protein (S100B), of pro-inflammatory molecules such as the monocyte chemoattractant proten-1 (MCP-1) and interleukin-6, and to increase the production of reactive oxygen species (ROS) via the expression of inducible nitric oxide synthase (iNOS). (c) In microglia, the signaling pathways upstream of p38 MAPK activation are very similar to those found in astrocytes. However, in addition, they lead to the production of pro-inflammatory cytokines such as interleukin-1β, the tumor necrosis factor α, and IL-6, and to increase ROS production, microglial activation of the p38 α isoform has been demonstrated to play a key role in the Aβ-dependent synaptic dysfunction.

Figure 2

Kinome target selectivity of p38 MAPK Inhibitors. Differences in off-target kinase and GPCR liabilities provide potential explanations for pharmacological differences. Red circles denote kinase inhibition below the canonical IC50 < 1 µM. (A) Common off-target kinases among widely used p38α MAPK inhibitors: VX-745 (neflamapimod) includes ABL1, ABL2, p38β, PDGFRβ, and SRC; BIRB-796 includes BLK, CDK5, CDK8, DDR1, DDR2, EPHA3, EPHA7, EPHA8, EPHB2, p38β p38γ, FLT1, FRK, NTRK1, JNK1, JNK2, JNK3, KIT, MAP4K4, MRCKβ, PTK2β, RET, SLK, STK10, TIE1, TIE2, TNIK, TRKB, TRKC, and ZAK; and SB203580 includes BRAF, CIT, CK1δ, CK1ε, DMPK, GAK, JNK2, JNK3, NLK, p38β, RIPK2, STK36, and TNIK. (B) MW150 and MW108 have IC50 <1 µM for p38α MAPK in kinome-wide hierarchal screens.