Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer's Disease

Abstract

P38 mitogen-activated protein kinase (MAPK) is a crucial target for chronic inflammatory diseases. Alzheimer's disease (AD) is characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain, as well as neurodegeneration, and there is no known cure. Recent studies on the underlying biology of AD in cellular and animal models have indicated that p38 MAPK is capable of orchestrating diverse events related to AD, such as tau phosphorylation, neurotoxicity, neuroinflammation and synaptic dysfunction. Thus, the inhibition of p38 MAPK is considered a promising strategy for the treatment of AD. In this review, we summarize recent advances in the targeting of p38 MAPK as a potential strategy for the treatment of AD and envision possibilities of p38 MAPK inhibitors as a fundamental therapeutics for AD.

Keywords: Alzheimer’s disease; amyloid beta; kinase inhibitor; neuroinflammation; p38 mitogen activated protein kinase (MAPK); tau phosphorylation.

Figure 1

Diverse roles of p38 MAPK in AD pathologies. (A) Amyloid-β (Aβ) plaques evoke neuronal damages including mitochondria dysfunction, apoptosis, tau phosphorylation and synaptic dysfunction via p38 MAPK activation; (B) Increased microglial p38 MAPK signaling induced by Aβ is a main driver of neuroinflammation in AD, leading to production of pro-inflammatory mediators, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Especially, IL-1β released from microglia stimulates p38 MAPK signaling of neuron and astrocyte in AD and exacerbates the AD brain pathology; (C) P38 MAPK activation in astrocyte is enhanced by Aβ plaques and IL-1β produced by microglia. This activation accelerates the neuroinflammation by releasing iNOS, COX-2 and TNF-α.

Figure 2

Binding modes of representative p38 MAPK inhibitors: (A) Binding mode of SB203580 (1) within p38 MAPKα; (B) Binding mode of BIRB796 (2) within p38 MAPKα.

Figure 3

Examples of novel compounds targeting Aβ and tau pathologies.

Figure 4

Schematic representation illustrating the tau phosphorylation sites by p38 MAPK.

Figure 5

Structures of the compounds known to inhibit tau phosphorylation by modulating the p38 MAPK pathway.

Figure 6

Natural compounds reducing Aβ-induced neurotoxicity via p38 MAPK inhibition.

Figure 7

Compounds reducing Aβ-induced neurotoxicity via p38 MAPK inhibition I.

Figure 8

Compounds reducing Aβ-induced neurotoxicity via p38 MAPK inhibition II.

Figure 9

Compounds reducing Aβ-induced neurotoxicity via p38 MAPK inhibition III.

Figure 10

Structures of compounds known to suppress inflammation in glia by modulating the p38 MAPK pathway.

Figure 11

Examples of recently reported potent and selective p38 MAPK inhibitors.