title: Nicastrin overexpression in transgenic mice induces aberrant behavior and APP processing.
abstract: Nicastrin (NCT) is a component of the presenilin protein complex, which is involved in the cleavage of β-amyloid precursor protein (βAPP) and Notch. The aim of this study was to determine the manner in which overexpression of wild-type human nicastrin (hNCTw) or mutant human nicastrin (hNCTm, D336A/Y337A) regulates brain functions and amyloid precusor protein (APP) processing. For this, we created transgenic (Tg) mice expressing neuron-specific enolase (NSE)-controlled hNCTw or hNCTm and measured their phenotypes as time passed. The NSE/hNCTw and NSE/hNCTm Tg groups exhibited greater behavioral dysfunction from 10 months of age than the non-Tg group, although their severities differed. Further, activity and component levels of the γ-secretase complex were significantly elevated in NSE/hNCTw Tg mice, expect for PEN-2. These alterations induced stimulation of APP processing, resulting in overproduction of Aβ-42 peptide in the NSE/hNCTw Tg group, whereas the NSE/hNCTm Tg group showed a comparatively weaker effect. Furthermore, the highest expression levels of β-secretase and NICD were observed in the NSE/hNCTw Tg group, similar to other phenotypes. Especially, a significances interference on the interaction between NCT and γ-secretase substrates was detected in NSE/hNCTm Tg groups compare with NSE/hNCTw Tg group. These results indicate that hNCTw overexpression in Tg mice promoted active assembly of the γ-secretase complex through modulation of APP processing and behavior, whereas the lesser effect in NSE/hNCTm Tg mice was due to reduced expression of hNCTm. These Tg mice could be useful for the development and application of therapeutic drugs in an animal model of Alzheimer's disease.
authors.affiliation: Department of Biomaterials Science, College of Natural Resources & Life Science, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup, Miryang-si, Gyeongsangnam-do, 627-706, Korea.
authors.forename: Jun Seo
authors.initials: JS
authors.lastname: Goo
authors.forename: Yong Bin
authors.initials: YB
authors.lastname: Kim
authors.forename: Sun Bo
authors.initials: SB
authors.lastname: Shim
authors.forename: Seung Wan
authors.initials: SW
authors.lastname: Jee
authors.forename: Su Hae
authors.initials: SH
authors.lastname: Lee
authors.forename: Ji Een
authors.initials: JE
authors.lastname: Kim
authors.forename: In Sik
authors.initials: IS
authors.lastname: Hwang
authors.forename: Young Ju
authors.initials: YJ
authors.lastname: Lee
authors.forename: Moon Hwa
authors.initials: MH
authors.lastname: Kwak
authors.forename: Chuel Ju
authors.initials: CJ
authors.lastname: Lim
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.forename: Dae Youn
authors.initials: DY
authors.lastname: Hwang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D004789:Enzyme Activation; D006801:Humans; D018782:Maze Learning; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051381:Rats; D013379:Substrate Specificity; D019076:Transgenes / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; D010455:Peptides; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases