Abstract
Alzheimer’s disease (AD) and other tauopathies are histopathologically characterized by tau aggregation, along with a chronic inflammatory response driven by microglia. Over the past few years, the role of microglia in AD has been studied mainly in relation to amyloid-β (Aβ) pathology. Consequently, there is a substantial knowledge gap concerning the molecular mechanisms involved in tau-mediated toxicity and neuroinflammation, thus hindering the development of therapeutic strategies. We previously demonstrated that extracellular soluble tau triggers p38 MAPK activation in microglia. Given the activation of this signaling pathway in AD and its involvement in neuroinflammation processes, here we evaluated the effect of p38 inhibition on primary microglia cultures subjected to tau treatment. Our data showed that the toxic effect driven by tau in microglia was diminished through p38 inhibition. Furthermore, p38 blockade enhanced microglia-mediated tau phagocytosis, as reflected by an increase in the number of lysosomes. In conclusion, these results contribute to our understanding of the functions of p38 in the central nervous system (CNS) beyond tau phosphorylation in neurons and provide further insights into the potential of p38 inhibition as a therapeutic strategy to halt neuroinflammation in tauopathies.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, affecting 47 million people worldwide
The analysis of cell death by flow cytometry confirmed these results (Supplementary Fig. S3), thereby indicating that p38 inhibition alleviates cytotoxicity in microglia treated with tau
Recent research conducted by our group revealed that tau triggers an inflammatory response in microglia through p38 activation [41]
Summary
Alzheimer’s disease (AD) is the most common form of dementia, affecting 47 million people worldwide. It is the main cause of dependence in older adults and the fifth cause. Tau protein is subjected to numerous post-translational modifications, phosphorylation being the most recurrent [13]. This process is physiologically regulated throughout life. The state of phosphorylation plays a very important role in regulating the physiological function of tau, since it reduces the binding affinity of tau to microtubules and promotes its aggregation, compromising the integrity of neurons [15, 16]. Several authors have reported that NFTs are not as toxic as previously believed, thereby suggesting that small aggregates and soluble tau species are the main drivers of neurodegeneration
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