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Licensed Unlicensed Requires Authentication Published by De Gruyter May 28, 2018

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

Ghazaleh Kheiri, Mahsa Dolatshahi, Farzaneh Rahmani and Nima Rezaei

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.

Acknowledgments

Tehran University of Medical Sciences supported this study.

  1. Conflict of interest statement: The authors declare no conflict of interest.

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Received: 2018-01-28
Accepted: 2018-03-22
Published Online: 2018-05-28
Published in Print: 2018-12-19

©2019 Walter de Gruyter GmbH, Berlin/Boston