Anesthesia-induced hyperphosphorylation detaches 3-repeat tau from microtubules without affecting their stability in vivo.
In Alzheimer's disease, tau is hyperphosphorylated, which is thought to detach it from microtubules (MTs), induce MT destabilization, and promote aggregation. Using a previously described in vivo model, we investigated whether hyperphosphorylation impacts tau function in wild-type and transgenic mice. We found that after anesthesia-induced hypothermia, MT-free tau was hyperphosphorylated, which impaired its ability to bind MTs and promote MT assembly. MT-bound tau was more resistant to hyperphosphorylation compared with free tau and tau did not dissociate from MTs in wild-type mice. However, 3-repeat tau detached from MT in the transgenic mice. Surprisingly, dissociation of tau from MTs did not lead to overt depolymerization of tubulin, and there was no collapse, or disturbance of axonal MT networks. These results indicate that, in vivo, a subpopulation of tau bound to MTs does not easily dissociate under conditions that extensively phosphorylate tau. Tau remaining on the MTs under these conditions is sufficient to maintain MT network integrity.
Planel
Emmanuel
E
Taub Institute for Alzheimer's Disease Research, Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA.
Krishnamurthy
Pavan
P
Miyasaka
Tomohiro
T
Liu
Li
L
Herman
Mathieu
M
Kumar
Asok
A
Bretteville
Alexis
A
Figueroa
Helen Y
HY
Yu
Wai Haung
WH
Whittington
Robert A
RA
Davies
Peter
P
Takashima
Akihiko
A
Nixon
Ralph A
RA
Duff
Karen E
KE
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D007036:Hypothermia, Induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D018911:Trinucleotide Repeats / Q000235:genetics; D016875:tau Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D000777:Anesthetics; D016875:tau Proteins