Internalization and Endosomal Trafficking of Extracellular Tau in Microglia Improved by α-Linolenic Acid.

Alzheimer's disease (AD) is distinguished by extracellular accumulation of amyloid-beta plaques and intracellular neurofibrillary tangles of Tau. Pathogenic Tau species are also known to display "prion-like propagation," which explains their presence in extracellular spaces as well. Glial population, especially microglia, tend to proclaim neuroinflammatory condition, disrupted signaling mechanisms, and cytoskeleton deregulation in AD. Omega-3 fatty acids play a neuroprotective role in the brain, which can trigger the anti-inflammatory pathways as well as actin dynamics in the cells. Improvement of cytoskeletal assembly mechanism by omega-3 fatty acids would regulate the other signaling cascades in the cells, leading to refining clearance of extracellular protein burden in AD. In this study, we focused on analyzing the ability of α-linolenic acid (ALA) as a regulator of actin dynamics to balance the signaling pathways in microglia, including endocytosis of extracellular Tau burden in AD.

Biochemical and Biophysical Characterization of Tau and α-Linolenic Acid Vesicles In Vitro.

Alzheimer's disease (AD) is characterized by the abnormal accumulation of disordered protein, that is, extracellular senile plaques of amyloid-ß (Aß) and intracellular neurofibrillary tangles of Tau. Tau protein has gained the attention in recent years owing to the ability to propagate in a "prion-like" nature. The disordered protein Tau possesses a high positive charge, which allows its binding to anionic proteins and factors. The native disorder of proteins attends the ß-sheet structure from its random-coiled conformation upon charge compensation by various polyanionic agents such as heparin, RNA, etc. Anionic lipids such as arachidonic acid (AA) and oleic acid (OA) are also one of the factors which can induce aggregation of Tau in physiological conditions. The free units of Tau protein can bind to lipid membranes through its repeat domain (RD), the anionic side chains of the membrane lipids induce aggregation of Tau by reducing the activation barrier. In this study, we investigated the role of α-linolenic acid (ALA) as an inducing agent for Tau aggregation in vitro conditions. Omega-3 fatty acids bear a capacity to reduce the pathology of Tau by downregulating the Tau phosphorylation pathway. We have studied by using various biochemical or biophysical methods the potency of ALA as an aggregating agent for Tau. We have implemented different techniques such as SDS-PAGE, transmission electron microscopy, CD spectroscopy to evaluated higher-order aggregates of Tau upon induction by ALA.

α-Linolenic Acid Induces Microglial Activation and Extracellular Tau Internalization.

Neuroinflammation is the brain condition that occurs due to the hyper-activation of brain's immune cells and microglia, over the stimulation of extracellular aggregated proteins such as amyloid plaques and by extracellular Tau as well. The phenotypic changes of microglia from inflammatory to anti-inflammatory can be triggered by many factors, which also includes dietary fatty acids. The classes of omega-3 fatty acids are the majorly responsible in maintaining the anti-inflammatory phenotype of microglia. The enhanced phagocytic ability of microglia might induce the clearance of extracellular aggregated proteins, such as amyloid beta and Tau. In this study, we emphasized on the effect of α-linolenic acid (ALA) on the activation of microglia and internalization of the extracellular Tau seed in microglia.