The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP.
The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP.
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DOI：
10.3233/jad-2008-15405
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Vitek MP
中科院分区：
文献类型：
--
作者：
Colton CA;Wilcock DM;Wink DA;Davis J;Van Nostrand WE;Vitek MP
Nitric oxide synthase 2 (NOS2) and its gene product, inducible NOS (iNOS) play an important role in neuroinflammation by generating nitric oxide (NO), a critical signaling and redox factor in the brain. Although NO is associated with tissue damage, it can also promote cell survival. We hypothesize that during long-term exposure to amyloid-β (Aβ) in Alzheimer’s disease (AD), NO levels fall in the brain to a threshold at which the protective effects of NO cannot be sustained, promoting Aβ mediated damage. Two new mouse models of AD have been developed that utilize this concept of NO’s action. These mice express human amyloid-β protein precursor (AβPP) mutations that generate Aβ peptides on a mouse NOS2 knockout background. The APP/NOS2−/− bigenic mice progress from Aβ production and amyloid deposition to hyperphosphorylated normal mouse tau at AD-associated epitopes, aggregation and redistribution of tau to somatodendritic regions of neurons and significant neuronal loss including loss of interneurons. This AD-like pathology is accompanied by robust behavioral changes. As APP/NOS2−/− bigenic mice more fully model the human AD disease pathology, they may serve as a tool to better understand disease progression in AD and the role of NO in altering chronic neurological disease processes.
