Granulovacuolar degeneration and unfolded protein response in mouse models of tauopathy and Aβ amyloidosis

Kohler, Christoph, Dinekov, Maja and Gotz, Jürgen (2014) Granulovacuolar degeneration and unfolded protein response in mouse models of tauopathy and Aβ amyloidosis. Neurobiology of Disease, 71 169-179. doi:10.1016/j.nbd.2014.07.006

Author Kohler, Christoph
Dinekov, Maja
Gotz, Jürgen
Title Granulovacuolar degeneration and unfolded protein response in mouse models of tauopathy and Aβ amyloidosis
Journal name Neurobiology of Disease   Check publisher's open access policy
ISSN 1095-953X
Publication date 2014-11
Year available 2014
Sub-type Article (original research)
DOI 10.1016/j.nbd.2014.07.006
Open Access Status
Volume 71
Start page 169
End page 179
Total pages 11
Place of publication Maryland Heights, MO, United States
Publisher Academic Press
Collection year 2015
Language eng
Abstract Histopathological studies on the brains of tauopathy cases including cases with Alzheimer's disease (AD) demonstrate that neurons with hyperphosphorylated protein tau display granulovacuolar degeneration (GVD), as evidenced by vacuolar lesions harboring a central granule, together with markers of the activated unfolded protein response (UPR). In order to examine whether this hallmark is reproduced in animal models we studied the presence of GVD and the activated UPR in two complementary mouse models, pR5 mice with a tau pathology and APPSLxPS1mut mice with an amyloid plaque pathology. Neither GVD nor a significant activation of the UPR was found in both APPSLxPS1mut mice and in those regions in the pR5 brain where only neurons with an early stage of tau hyperphosphorylation were present. In contrast, those neurons that displayed a tau phospho-epitope signature that only appeared in old pR5 mice and also correlated with Gallyas-positive tangle staining harbored granulovacuolar lesions that were labeled with the GVD markers casein kinases 1δ and 1ε. Granulovacuolar lesions in pR5 mice were also labeled with the UPR markers phosphorylated PKR-like endoplasmic reticulum kinase, phosphorylated inositol-requiring enzyme 1α and phosphorylated eukaryotic initiation factor 2α. However, GVD was rarely observed in neurons bearing mature neurofibrillary tangles as evidenced by Congo red staining. Our results suggest that NFT-formation activates the UPR in pR5 mice and that it is the early stages of neurofibrillary tangle formation that are accompanied by GVD, in line with observations from studies on human autopsy cases.
Keyword Activating transcription factor 4 (ATF4)
Alzheimer's disease
Casein kinase 1δ
Casein kinase Iε
Endoplasmic reticulum (ER) stress
Eukaryotic initiation factor 2α (eIF2α)
Inositol-requiring enzyme 1α (IRE1α)
PKR-like endoplasmic reticulum kinase (PERK)
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2015 Collection
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Citation counts: TR Web of Science Citation Count  Cited 10 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 9 times in Scopus Article | Citations
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