Abstract
Tau aggregates are pleiotropic and exhibit differences in conformation, structure, and size. These aggregates develop endogenously but are also propagated among neurons in disease. We explored the actions of two distinct types of tau aggregates, tau oligomers (oTau) and tau fibrils (fTau), using a seeding assay in primary neuron cultures expressing human 4R0N tau. We find that oTau and fTau elicit distinct patterns of tau inclusions in the neurons and distinct molecular interactions. The exogenously applied oTau and fTau both clear rapidly from the neurons, but both also seed intracellular inclusions composed of endogenously produced tau. The two types of seeds elicit differential dose–response relationships for seed uptake and the number of resulting intracellular inclusions. Immunocytochemical studies show that co-localization with RNA binding proteins associated with stress granules is much greater for seeds composed of oTau than fTau. Conversely, co-localization with p62/SQSTM1 and thioflavine S is much greater for fTau than oTau. These results suggest that oTau seeds inclusions that modulate the translational stress response and are physiologically active, whereas fTau seeds inclusions that are fibrillar and shunted to the autolysosomal cascade.
Highlights
The microtubule association protein tau is one of the principal components of pathology in Alzheimer’s disease and related disorders (ADRD) [1]
This study showed a striking association between tau oligomers and RNA binding protein (RBP) pathology [19]
Data are shown as mean ± SEM, N = 20, data analysis was by one-way ANOVA, multiple comparison test by Fisher’s LSD, *p < 0.05, **p < 0.01 in comparison with vehicle control. (C) Representative images showing the co-localization of phosphorylated tau inclusions CP13 with PABP granules at 3 h after oligomeric tau (oTau), fibrillar tau (fTau), or vehicle treatment in hippocampal neurons overexpressing human 4R0N tau
Summary
The microtubule association protein tau is one of the principal components of pathology in Alzheimer’s disease and related disorders (ADRD) [1]. Tau exists primarily in the axon under basal conditions, with smaller amounts in the dendritic arbor. Stress induces phosphorylation of tau and localization to the somato-dendritic compartment [2, 3]. The tau begins to accumulate as oligomers and fibrils, forming neurofibrillary tangles, which are a pathological hallmark of Alzheimer’s disease and other tauopathies. Our understanding of the patterns and properties of tau aggregates has evolved steadily. In vitro studies showed that tau exhibits an intrinsic affinity for RNA, an anionic agent, and a tendency to fibrillize in the presence of anionic agents, including RNA, heparin sulfate, dextran sulfate, and arachidonic acid [4,5,6]. Aggregation of purified tau with anionic agents
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