Aberrant tau phosphorylation by glycogen synthase kinase-3beta and JNK3 induces oligomeric tau fibrils in COS-7 cells.
Neurofibrillary tangles (NFTs) are found in a wide range of neurodegenerative disorders, including Alzheimer's disease. The major component of NFTs is aberrantly hyperphosphorylated microtubule-associated protein tau. Because appropriate in vivo models have been lacking, the role of tau phosphorylation in NFTs formation has remained elusive. Here, we describe a new model in which adenovirus-mediated gene expression of tau, DeltaMEKK, JNK3, and GSK-3beta in COS-7 cells produces most of the pathological phosphorylation epitopes of tau including AT100. Furthermore, this co-expression resulted in the formation of tau aggregates having short fibrils that were detergent-insoluble and Thioflavin-S-reactive. These results suggest that aberrant tau phosphorylation by the combination of these kinases may be involved in "pretangle," oligomeric tau fibril formation in vivo.
Sato
Shinji
S
Laboratory for Alzheimer's Disease, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Tatebayashi
Yoshitaka
Y
Akagi
Takumi
T
Chui
De-Hua
DH
Murayama
Miyuki
M
Miyasaka
Tomohiro
T
Planel
Emmanuel
E
Tanemura
Kentaro
K
Sun
Xiaoyan
X
Hashikawa
Tsutomu
T
Yoshioka
Katsuji
K
Ishiguro
Koichi
K
Takashima
Akihiko
A
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D048057:Mitogen-Activated Protein Kinase 10; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D048057:Mitogen-Activated Protein Kinase 10; D011505:Protein-Tyrosine Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3