Role of p38/MAPKs in Alzheimer’s disease: implications for amyloid beta toxicity targeted therapy

Abstract

A myriad of environmental and genetic factors, as well as the physiologic process of aging, contribute to Alzheimer's disease (AD) pathology. Neuroinflammation is and has been a focus of interest, as a common gateway for initiation of many of the underlying pathologies of AD. Amyloid beta (Aβ) toxicity, increasing RAGE expression, tau hyperphosphorylation, induction of apoptosis, and deregulated autophagy are among other mechanisms, partly entangled and being explained by activation of mitogen-activated protein kinase (MAPK) and MAPK signaling. p38 MAPK is the most essential regulator of Aβ induced toxicity from this family. p38 induces NF-κB activation, glutamate excitotoxicity, and disruption of synaptic plasticity, which are other implications of all justifying the p38 MAPK as a potential target to break the vicious Aβ toxicity cycle. Until recently, many in vivo and in vitro studies have investigated the effects of p38 MAPK inhibitors in AD. The pyridinyl imidazole compounds SB202190 and SB203580 have shown promising anti-apoptotic results in vivo. MW108 inhibits activation of p38 and is able to postpone cognitive decline in animal models. The PD169316, with anti-inflammatory, anti-oxidative, and anti-apoptotic features, has improved spatial memory in vivo. Natural compounds from Camellia sinensis (green tea), polyphenols from olive oil, pinocembrin from propolis, and the puerarine extract isoflavones, have shown strong anti-apoptotic features, mediated by p38 MAPK inhibition. Use of these drug targets is limited due to central nervous system side effects or cross-reactivity with other kinases, predicting the low efficacy of these drugs in clinical trials.

Role of Alterations in Protein Kinase p38γ in the Pathogenesis of the Synaptic Pathology in Dementia With Lewy Bodies and α-Synuclein Transgenic Models

“…Aberrant activation of p38α has been extensively studied in AD as an important trigger for amyloid-β-mediated neuroinflammation, tau hyper-phosphorylation, and excitotoxicity (Bachstetter and Van Eldik, 2010;Lloret et al, 2015;Maphis et al, 2016;Lee and Kim, 2017;Kheiri et al, 2018). Inhibition of p38α, but not β, has been shown to be protective in models of AD (Xing et al, 2015;Lee and Kim, 2017;Kheiri et al, 2018). In PD, abnormal p38α and β activity may also mediate the deleterious effects of environmental toxins on dopaminergic neurons and promote neuro-inflammation via microglia (Jha et al, 2015;Kim and Choi, 2015;He et al, 2018).…”

scGRNom: a computational pipeline of integrative multi-omics analyses for predicting cell-type disease genes and regulatory networks

“…In AD, multiple forms of chemical transmission and neuronal cell regulation were found to contribute to the neurodegenerative nature of the disease: transmission across chemical synapses (p<1.04e-12) [51,52] as well regulation of synaptic plasticity (p<1.12e-9) [52,53], dendrite development (p<1.01e-8) [53,54], and postsynapse organization (p<1.12e-9) [55]. Similarly, when examining inhibitory neurons within the context of AD progression we noted additional forms of signaling and regulatory pathways as enriched: glutamatergic synapses (p<4.22e-10) [55], MAPK signaling (p<2.38e-4) [36], and NMDA receptor activity regulation (p<7.19e-5) [29]. Lastly, SCZ enrichment for both excitatory and inhibitory neurons were similar to those of AD, possessing unique, diseasespecific interactions.…”

“…The majority of the microglia-based functionality revolves around the standard operations of the cell primarily concerning neuroimmune response elements of disease pathology. For example, in AD, we observed known key pathways surrounding the functional consequences of Amyloid Beta formation (p<3.21e-6) [35] including MAPK1/MAPK3 signaling (p<3.92e-8) [36] and neurite growth (axonogenesis) (p<2.23e-14) [37]. In a similar path, the oligodendrocyte analysis reveals Tau protein binding (p< 1.72e-5) [38] and tubulin binding (p<2.29e-4) [39] are heavily associated with the enrichment.…”

A selective p38α/β MAPKs inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse

“…P38 MAPKs inhibition is one of the promising targets for AD therapy. Numerous studies have attempted to attenuate Aβ-induced neurotoxicity and memory impairment through inhibition of the p38 MAPKs signaling [50,51]. Recent reports using selective p38α MAPK inhibitors, neflamapimod (VX-745), MW150, and MW181, have shown potential therapeutic effects for AD.…”