The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP - PubMed (original) (raw)

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The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP

Carol A Colton et al. J Alzheimers Dis. 2008 Dec.

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.

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Figures

Figure 1

Figure 1

Panel A: Average fold change (± SEM) in mRNA levels of pro-inflammatory (TNFα; NOS2) and repair [arginase 1 (AG1) and chitinase 3-like-1 (CH3L1)] cytokines from mixed cortical lysates from humans with AD (average age approximately 78 yrs; Stage 4–5 Braak scale). Quantitative RT-PCR data from AD samples were compared to brain samples from aged matched normal individuals. De-identified autopsied brain samples were provided by the Kathleen Bryan Brain Bank at Duke University Medical Center, Durham, NC as described [30]. Panel B: Average fold change (± SEM) in mRNA from aged (52–54 week old) APPSwDI/NOS2−/− mice compared to aged matched wild type (WT) mice. Pro-inflammatory genes were TNFα and IL-6 and repair genes were AG1 and YM1 (mouse homolog for CH3L1). All values are significantly greater than control with p ≤ 0.05 (Student’s t test) (for humans, n = 29 control; AD; mixed gender; for mice n = 5–6 mice, mixed gender).

Figure 2

Figure 2

Neuronal loss in APPSw/NOS2−/− compared to APPSw mice at 52–54 weeks of age. A,C,E = tyical views of hippocampus in APPSw mice. B,D,F = same areas in APPSw/NOS2−/− mice. Neurons were identified using NeuN immunochemistry. G: Unbaised stereology was used to count neurons in specific brain regions. A significant decrease (*** = p < 0.001) was observed in all regions in the APPSw/NOS2−/− (abbreviated AN2) mice compared to APPSw (abbreviated A), WT, NOS2−/− (abbreviated N2) mice. H: Summary of the percent changes in neuronal number.

Figure 3

Figure 3

Behavioral deficits in the APPsw/NOS2−/− compared to APPSw mice at 52–54 weeks age. The 2-day radial arm water maze was used to test learning and memory as described [136]. Data points represent the average (± SEM) number of errors in each of the 5 blocks of trials on day 2 of the testing paradym. *** p < 0.001 compared to either NOS2−/− or to APPSw, n = 7–14 mice/group.

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