AbstractA 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, manyin vivoandin vitrostudies have investigated the effects of p38 MAPK inhibitors in AD. The pyridinyl imidazole compoundsSB202190andSB203580have shown promising anti-apoptotic resultsin vivo. MW108inhibits activation of p38 and is able to postpone cognitive decline in animal models. ThePD169316, with anti-inflammatory, anti-oxidative, and anti-apoptotic features, has improved spatial memoryin vivo. Natural compounds fromCamellia 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.
p38 MAPK‐mediated loss of nuclear RNase III enzyme Drosha underlies amyloid beta‐induced neuronal stress in Alzheimer's disease