Accumulation of Vesicle-Associated Human Tau in Distal Dendrites Drives Degeneration and Tau Secretion in an In Situ Cellular Tauopathy Model
The mechanism of tau-induced dendritic degeneration in ABCs. (a) Schematic summarizing the hypothesized sequence of events leading to tau-induced degeneration in ABC dendrites. Low-level exogenous tau expression (1) does not saturate the tau:tubulin binding sites on dendritic MTs, permitting all exogenous tau to bind directly to dendritic MTs (green arrows) and remain poorly phosphorylated and nontoxic. (2) In ABCs expressing enough exogenous tau to saturate existing MTs, excess tau becomes phosphorylated at the 9G3 and 12E8 sites and associated with trafficking vesicles. These are transported distally to and accumulate in the relatively MT-poor dendritic tips, where they induce degeneration, possibly by being secreted to form toxic extracellular deposits. (3) The consequent increased intracellular Ca2+, MT destabilization, misdistribution of mitochondria, and cytoskeletal aggregation become self-perpetuating (4, red arrows), driving progressive dendritic degeneration (black). (b) Colocalization of MT loss and non-MT-associated tau accumulation. A -axis reconstruction of a dendrite (left) containing a bundle of MTs along which tau was being transported distally (1–5) and accumulating (6–11) at the POD. The distribution of total tau (GFP tag, red) and non-MT-associated tau (9G3, blue) is shown versus tubulin (green). Numbers correspond to the sites in the original stack (left) chosen for cross-sectional views (right and bottom). Note that MTs (asterisks, 3) rapidly become more saturated with tau between sections 1 and 3. Above the tau-MT saturation point (3, caret), the MT bundles lose tubulin label over a very short distance (black arrows, 4 and 5). Scale bar: 2 μm.
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