Novel therapeutic inhibitor targeting dysregulated kinase signaling in tau-mediated neurodegeneration

Abstract

In the case of tauopathies (like Alzheimer's disease), there is a progressive deterioration of neurons in association with abnormal tau hyperphosphorylation followed by destabilization of microtubules and the formation of neurofibrillary tangles. A variety of dysregulated kinase signaling pathways have been heavily implicated in the regulation of tau phosphorylation and disease progression, such as those involving glycogen synthase kinase 3β (GSK 3β), cyclin dependent kinase 5 (CDK5) and mitogen activated protein kinases (MAPKs). In this context, the MAPK/ERK signaling pathway, in particular ERK1/2, has been identified as a key pathway involved in regulating tau-associated processes, neuronal plasticity and survival and is of particular interest in Tau mediated neurodegeneration. In this review, the molecular mechanisms and the connection between kinase regulation, synaptic dysfunction and tau pathology are discussed, especially with regard to ERK1/2-mediated signaling. Previous studies have shown that HEK1/2 modulation can be implicated in tau phosphorylation pathways and has implications as a therapeutic target. Further, preclinical studies using natural compounds like Baicalein have been conducted to show their possible neuroprotective effects, but they need to be further tested in experiments to confirm their efficacy, target engagement and therapeutic relevance in tauopathies. In general, this review emphasizes the roles of kinase signaling pathways in tau mediated neurodegeneration and suggests ERK1/2 as an interesting therapeutic target. Additional in vitro, in vivo and clinical research is needed to assess the translatability of ERK1/2 targeting strategies for disease modifying treatment in tauopathies.