Publication Date:
2022-05-25
Description:
Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of John Wiley & Sons for personal use, not for redistribution. The definitive version was published in Journal of Neuroscience Research 87 (2009): 440-451, doi:10.1002/jnr.21850.
Description:
The neuropathology of Alzheimer’s disease (AD) and other tauopathies is characterized
by filamentous deposits of the microtubule-associated protein tau, but the relationship between
tau polymerization and neurotoxicity is unknown. Here, we examined effects of filamentous tau
on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric and filamentous forms
of recombinant human tau were perfused in axoplasm, and their effects on kinesin- and dyneindependent
FAT rates evaluated by video microscopy. While perfusion of monomeric tau at
physiological concentrations showed no effect, tau filaments at the same concentrations
selectively inhibited anterograde (kinesin-dependent) FAT, triggering the release of conventional
kinesin from axoplasmic vesicles. Pharmacological experiments indicated that the effect of tau
filaments on FAT is mediated by protein phosphatase 1 (PP1) and glycogen synthase kinase-3
(GSK-3) activities. Moreover, deletion analysis suggested that these effects depend on a
conserved 18-amino acid sequence at the amino terminus of tau. Interestingly, monomeric tau
isoforms lacking the C-terminal half of the molecule (including the microtubule binding region)
recapitulated the effects of full-length filamentous tau. Our results suggest that pathological tau
aggregation contributes to neurodegeneration by altering a regulatory pathway for FAT.
Description:
Research supported by NIH awards NS049834 (N.E.L.),
AG14453 (L.I.B.), NINDS grants NS23868, NS23320, NS41170 and NS43408 (S.B.), MDA
(S.B.), ALSA (G.M, S.B), and HDSA (G.M.).
Keywords:
Alzheimer's disease
;
Axonal transport
;
Tau filament
;
GSK3
;
PP1
;
Kinesin
;
Tau
Repository Name:
Woods Hole Open Access Server
Type:
Preprint
Format:
application/pdf
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