Nicastrin Overexpression in Transgenic Mice Induces Aberrant Behavior and APP Processing

作者：Goo Jun Seo; Kim Yong Bin; Shim Sun Bo; Jee Seung Wan; Lee Su Hae; Kim Ji Een; Hwang In Sik; Lee Young Ju; Kwak Moon Hwa; Lim Chuel Ju; Hong Jin Tae; Hwang Dae Youn^*

来源：Molecular Neurobiology, 2013, 48(1): 232-243.

DOI：10.1007/s12035-013-8453-3

• Nicastrin
• A beta-42
• Alzheimer%26apos
• s disease
• gamma-Secretase
• Transgenic mice

Nicastrin (NCT) is a component of the presenilin protein complex, which is involved in the cleavage of beta-amyloid precursor protein (beta APP) 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 gamma-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 A beta-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 beta-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 gamma-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 gamma-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%26apos;s disease.

• 出版日期2013-8