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The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP
Carol A Colton1, Donna M Wilcock, David A Wink
1Division of Neurology, Duke University Medical Center, Durham, NC 27710, USA. glia01@aol.com
Abstract:
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-beta (Abeta) 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 Abeta mediated damage. Two new mouse models of AD have been developed that utilize this concept of NO's action. These mice express human amyloid-beta protein precursor (AbetaPP) mutations that generate Abeta peptides on a mouse NOS2 knockout background. The APP/NOS2(-/-) bigenic mice progress from Abeta 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.
Insights
Alzheimer's disease (AD) involves amyloid-beta (Abeta) and reduced nitric oxide (NO). New bigenic mice lacking inducible nitric oxide synthase (NOS2) show AD pathology, suggesting NO deficiency exacerbates neuroinflammation and neuronal loss in AD.
Area of Science:
- Neuroscience
- Neuroinflammation
- Alzheimer's Disease Pathogenesis
Background:
- Inducible nitric oxide synthase (iNOS/NOS2) generates nitric oxide (NO), a key signaling molecule in the brain.
- NO has dual roles, potentially causing damage or promoting cell survival.
- In Alzheimer's disease (AD), chronic amyloid-beta (Abeta) exposure may lower NO levels, impairing its protective functions.
Purpose of the Study:
- To investigate the role of NO deficiency in Alzheimer's disease (AD) progression.
- To develop and characterize novel mouse models of AD with altered NOS2 expression.
Main Methods:
- Generation of bigenic mice expressing human amyloid-beta protein precursor (AbetaPP) mutations on a NOS2 knockout background (APP/NOS2(-/-)).
- Assessment of Abeta production, amyloid deposition, tau pathology (hyperphosphorylation, aggregation, redistribution), and neuronal loss.
- Evaluation of behavioral changes in the developed AD mouse models.
Main Results:
- APP/NOS2(-/-) bigenic mice exhibited Abeta production and amyloid deposition.
- These mice developed AD-like tau pathology, including hyperphosphorylation and aggregation.
- Significant neuronal loss, particularly interneurons, and associated behavioral deficits were observed.
Conclusions:
- The APP/NOS2(-/-) bigenic mouse model recapitulates key aspects of human AD pathology.
- This model highlights the detrimental role of NOS2 deficiency in exacerbating Abeta-mediated neuroinflammation and neurodegeneration.
- These mice serve as a valuable tool for studying AD progression and the impact of NO on chronic neurological diseases.
