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Nicastrin Overexpression in Transgenic Mice Induces Aberrant Behavior and APP Processing

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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.

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Acknowledgments

We thank Sun M. Choi, B.S. and Mi K. Jang, M.S., animal technicians, for directing the animal facility at the Division of Laboratory Animal Resources.

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Authors and Affiliations

  1. 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

    Jun Seo Goo, Ji Een Kim, In Sik Hwang, Young Ju Lee, Moon Hwa Kwak & Dae Youn Hwang

  2. Department of Laboratory Animal Resources, National Institute of Food and Drug Safety Evaluation, Korea FDA, Osong, 363-700, Korea

    Yong Bin Kim, Sun Bo Shim, Seung Wan Jee, Su Hae Lee & Chuel Ju Lim

  3. College of Pharmacy, Chungbuk National University, Chungju, 361-763, Korea

    Jin Tae Hong

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  1. Jun Seo Goo
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Correspondence to Dae Youn Hwang.

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Jun Seo Goo and Yong Bin Kim these authors equally contributed to this work.

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Goo, J.S., Kim, Y.B., Shim, S.B. et al. Nicastrin Overexpression in Transgenic Mice Induces Aberrant Behavior and APP Processing. Mol Neurobiol 48, 232–243 (2013). https://doi.org/10.1007/s12035-013-8453-3

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  • DOI: https://doi.org/10.1007/s12035-013-8453-3

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