Changes in presenilin 2-binding Wnt proteins, behavior, amyloid-beta 42, gamma-secretase activity, and testosterone sensitivity in transgenic mice coexpressing tetracycline-controlled transactivator and human mutant presenilin 2.
Nonregulatable promoters have been mainly used to produce transgenic mice that express the human genes for Alzheimer's disease (AD). The aim of this study was to produce doubly transgenic mice expressing the regulatable tet promoter-controlled transactivator (tTA) and human mutant presenilin 2 (N141I, hPS2m) genes in order to examine the AD-related phenotypes at the basal and inducible levels. To achieve this, the first lineage of the transgenic line, expressing Tet/tTA and the second lineage of transgenic mice, expressing Tet/hPS2m, were created, and the doubly transgenic mice were produced by crossing the Tet/tTA-transgenic mice with the Tet/hPS2m-transgenic mice. The doubly transgenic mice and nontransgenic littermates were then treated with or without doxycycline. The results showed that removing doxycycline from the transgenic mice resulted in the induction of the transgene, a Wnt signaling defect, behavioral impairment, elevated amyloid-beta-42 and gamma-secretase activity compared with in the group given doxycyline. Moreover, the expression levels of the hPS2m transgene decreased gradually in the transgenic males, with clear changes becoming apparent between 2 and 4 wk of age. Castrating these males resulted in an increased expression level of the hPS2m gene. This was restored to the normal levels by treatment with testosterone. Therefore, tetregulated transgenic mice can be used to examine the effect of the basal or inducible expression levels of hPS2m on the pathology of AD at the "on/off" states at any stage of development.
Hwang
Dae Y
DY
Division of Laboratory Animal Resources, Korea Food and Drug Administration, 122-704, Seoul, Korea.
Cho
Jung S
JS
Kim
Chuel K
CK
Shim
Sun B
SB
Jee
Seung W
SW
Lee
Su H
SH
Seo
Su J
SJ
Choi
Soo Y
SY
Kim
Yong K
YK
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*; D053766:Presenilin-2 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*; D014018:Tissue Distribution; D051153:Wnt Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D053766:Presenilin-2; D012097:Repressor Proteins; D051153:Wnt Proteins; C075222:amyloid beta-protein (1-42); C034811:tetracycline resistance-encoding transposon repressor protein; D013739:Testosterone; D053829:Amyloid Precursor Protein Secretases