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.
Laboratory for Alzheimer's Disease, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
Shinji
S
Sato
Yoshitaka
Y
Tatebayashi
Takumi
T
Akagi
De-Hua
DH
Chui
Miyuki
M
Murayama
Tomohiro
T
Miyasaka
Emmanuel
E
Planel
Kentaro
K
Tanemura
Xiaoyan
X
Sun
Tsutomu
T
Hashikawa
Katsuji
K
Yoshioka
Koichi
K
Ishiguro
Akihiko
A
Takashima
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