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Nicastrin overexpression in transgenic mice induces aberrant behavior and APP processing
Jun Seo Goo1, Yong Bin Kim, Sun Bo Shim
1Department of Biomaterials Science, College of Natural Resources & Life Science, Pusan National University, 50 Cheonghak-ri, Samnangjin-eup, Miryang-si, Gyeongsangnam-do, 627-706, Korea.
Molecular Neurobiology
|April 19, 2013
Summary
Overexpression of wild-type nicastrin (NCT) in mice enhanced gamma-secretase activity, increasing amyloid-beta 42 peptide production and behavioral dysfunction, suggesting a potential Alzheimer's disease model.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Nicastrin (NCT) is a key component of the presenilin complex, crucial for cleaving amyloid precursor protein (APP) and Notch.
- Dysregulation of APP processing is implicated in Alzheimer's disease pathogenesis.
Purpose of the Study:
- To investigate how overexpression of wild-type human nicastrin (hNCTw) and a mutant form (hNCTm) affects brain function and APP processing.
- To establish transgenic mouse models for studying Alzheimer's disease.
Main Methods:
- Created transgenic (Tg) mice expressing neuron-specific enolase (NSE)-controlled hNCTw or hNCTm.
- Assessed behavioral phenotypes and measured gamma-secretase complex activity, APP processing, and related protein levels.
Main Results:
- Both NSE/hNCTw and NSE/hNCTm Tg mice showed behavioral dysfunction starting at 10 months.
- NSE/hNCTw Tg mice exhibited elevated gamma-secretase activity, leading to Aβ-42 overproduction and increased beta-secretase and NICD levels.
- NSE/hNCTm Tg mice showed a weaker effect, attributed to reduced hNCTm expression and interference with NCT-substrate interactions.
Conclusions:
- hNCTw overexpression promotes gamma-secretase assembly and APP processing, impacting behavior.
- The mutant hNCTm had a lesser effect due to reduced expression and substrate interaction interference.
- These Tg mice serve as valuable models for developing Alzheimer's disease therapeutics.
