title: Granulovacuolar degeneration and unfolded protein response in mouse models of tauopathy and Aβ amyloidosis.
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.
authors: Institute II for Anatomy, Medical Faculty, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany. Electronic address: c.koehler@uni-koeln.de.
authors: Christoph
authors: C
authors: Köhler
authors: Institute II for Anatomy, Medical Faculty, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.
authors: Maja
authors: M
authors: Dinekov
authors: Clem Jones Centre for Ageing Dementia Research (CADR), Queensland Brain Institute (QBI), The University of Queensland, Brisbane (St Lucia Campus), QLD 4072, Australia.
authors: Jürgen
authors: J
authors: Götz
mesh_terms: D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D048148:Casein Kinase Idelta / Q000378:metabolism; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology* / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics; D024801:Tauopathies / Q000150:complications / Q000378:metabolism / Q000473:pathology; D056811:Unfolded Protein Response / Q000235:genetics*; D014617:Vacuoles / Q000473:pathology*; D019892:eIF-2 Kinase / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D048148:Casein Kinase Idelta; D053764:Presenilin-1; D019892:eIF-2 Kinase; D016875:tau Proteins; C054369:MAPT protein, human
keywords: AT100; 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)