NSE-controlled carboxyl-terminus of APP gene over-expressing in transgenic mice induces altered expressions in behavior, Abeta-42, and GSK3beta binding proteins.
The amyloid protein precursor (APP) is cleaved in its intramembranous domain by gamma-secrease to generate amyloid beta and a free carboxyl-terminal intracellular fragment. The carboxyl-terminal of 105 amino acids of APP (APP-C105) plays a crucial role in the neuropathology of Alzheimer's disease (AD), but it is incompletely understand how APP-C105 overexpression interacts and regulates the brain function and Abeta-42 levels, and whether or not it is associated with the expressions of GSK3beta-binding proteins. To test this, transgenic mice expressing NSE-controlled APP-C105 were produced and tested for their above phenotypes. A behavioral deficit was observed in the 9 months old transgenic mice, and western blot indicated that there was a predominant expression of APP-C105 in transgenic brains compared with those of non-transgenic brains. In parallel, APP-C105 overexpression resulted in the modulation of the Abeta-42 level, gamma-secretase activity, GSK3beta-binding proteins including PS1, tau, and beta-catenin in the brains of the transgenic mice relative to the non-transgenic mice. Thus, altered expressions of these neuropathological phenotypes in APP-C105 transgenic mice could be useful targets in developing new therapeutic treatments.
Lim
Hwa J
HJ
Division of Laboratory Animal Resources, Korea Food and Drug Administration, National Institute of Toxicological Research, 5 Nokbun-dong Eunpyng-ku, Seoul 122-704, Republic of Korea.
Cho
Jung S
JS
Oh
Jae H
JH
Shim
Sun B
SB
Hwang
Dae Y
DY
Jee
Seung W
SW
Lee
Su H
SH
Sheen
Yhun Y
YY
Lee
Seok H
SH
Kim
Yong K
YK
D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary; D019076:Transgenes / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D010751:Phosphopyruvate Hydratase