Accumulation of Vesicle-Associated Human Tau in Distal Dendrites Drives Degeneration and Tau Secretion in an In Situ Cellular Tauopathy Model
The state of tau:tubulin colocalization defines the threshold for tau-induced toxicity in ABCs. (a–c) illustrate the correlation between tau:tubulin colocalization pattern and neurodegenerative stage . (a) shows a typical example of low (left cell) and high (right cell) expression in the same section, permitting a direct comparison of staining intensity (DAB). Note that much of the heaviest tau staining in the high expressing cell occurs near the plasma membrane instead of colocalizing with the dendritic cytoskeleton. In particular, the tau label in the low expressing cell excludes the ventral soma, while this region stains heavily in the high expressing cell. (b) Images of tubulin (green) and tau (red) immunolabel from proximal dendrites illustrate the criteria used to assign ABCs to “low” and “high” expressing categories as described in the Methods section. Bottom images show colocalized voxels (colocalization highlighter, ImageJ) in the blue channel. With low tau expression (left and center pairs), exogenous tau was largely colocalized to endogenous MTs in the proximal dendrites, whereas in “high” tau expression, much of the tau label was distributed in areas devoid of tubulin label. (c) A comparison between the distribution of tau (GFP tag, red channel) and tubulin (DM1A, green channel) immunolabel in somatodendritic profiles of low-stage (left) and high-stage (right) ABCs. This clearly shows the relationship between MT saturation state with tau in large proximal dendrites and the stage of tau-induced degeneration. Note that only the distalmost dendrites of the ABC at the left (swollen, but not beaded) have accumulated high levels of tau, whereas the cell at the right is exhibiting both dendritic beading and some tau secretion (inset, asterisk). (d) The correlation between the level of tau expression and tau-induced degeneration was found to define the threshold level of tau expression above which tau is toxic to ABCs. The correlation between ABCs that exhibited “above saturation” levels of tau in proximal dendrites and those exhibiting significant beading and fragmentation of tertiary and quaternary dendrites (Stage 2 or greater of degeneration) was virtually without exception and was highly significant (, chi-square test). (e) Quantitative analysis of the effect of tau expression on total, tyrosinated and acetylated tubulin is shown for the axon (left) and dendrites (right). Tau overexpression had little effect on axonal tubulin levels but significantly reduced both total and tyrosinated tubulin levels and most prominently in normally MT-rich proximal dendrites (right). No effect was seen for acetylated tubulin staining in the dendrites (not shown). Scale bars: (b) 10 μm, (c) 50 μm.
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