Accumulation of Vesicle-Associated Human Tau in Distal Dendrites Drives Degeneration and Tau Secretion in an In Situ Cellular Tauopathy Model
High-resolution confocal images of “focal” tau secretion from ABCs. (a) High magnification imaging of surface rendered (ImageJ 3D Viewer) images of dendrites near the POD show significant colocalization between fyn and tau (left) in what appear to be exocytotic profiles (yellow). Active tau secretion via exocytosis can be identified in high-magnification confocal images of the surfaces of dendrites proximal to the POD in conjunction with the secretion of fyn-positive vesicles. Selective inclusion of 9G3 in secreted tau can be seen in exocytosing profiles from intact dendrites near the POD (right). (b) The autophagy marker LC3 undergoes secretion from ABC dendrites in a process that appears largely independent of tau (left), but higher resolution images show low levels of tau found in LC3+ vesicles that appear to be undergoing exocytosis (blue). (c) The gross appearance of tau leaving ABC dendrites suggests secretion via a membrane “shedding” mechanism (asterisks). Note that, in the right-hand image, this is not associated with the release of 9G3+ tau (vesicles, arrows), but rather with GFP-tau (red), which selectively colocalizes with exocytotic profiles (left, center, asterisks) (d) The main panel of d shows a dendrite triple-labeled with phalloidin (f-actin) and both total (anti-GFP-tag—red) and Tau12+ tau (blue). Only the phalloidin label that colocalized with tau is shown (colocalization highlighter, ImageJ), revealing phalloidin-tau+ vesicles that appear to be undergoing exocytosis (asterisks). When Tau12 and GFP channels are separated (insets), the relative exclusion of MT-associated tau relative to the GFP-tau from exocytosis profiles is evident (arrows). (e) While tau lacks typical features (signal peptide, acylation sites) of proteins that undergo conventional secretion, the well-established association of tau with fyn and other lipid raft-associated tyrosine kinases suggests some “unconventional” secretion mechanisms for tau protein, including both microvesicular and exosomal routes, both of which could involve cosecretion of tau and fyn. (f) The images shown in (a–d) suggest that multiple unconventional secretion pathways are involved in “focal” tau secretion from ABC dendrites. These include the direct shedding of microvesicles containing raft proteins (left), the generation of multivesicular bodies via raft “patching” and endocytosis, followed by MVB exocytosis and exosome release (center), and a recently identified variant of the exosomal pathway (exophagy) which involves autophagosomal fusion before exosome release (right). Scale bars (a) 5 μm, (b) 20 μm, (c) 5 μm.
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