Affiliations: [a] Division of Neurology, Duke University Medical Center, Durham, NC, USA | [b] Radiation Biology Branch, NCI, NIH, Bethesda, MD, USA | [c] Department of Medicine, Stony Brook University, Stony Brook, NY, USA
Correspondence:
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Corresponding author: Carol A. Colton, Division of Neurology, Box 2900, Duke University Medical Center, Durham, NC 27710, USA. Tel.: +1 919 668 2758; Fax: +1 919 684 6514; E-mail: 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-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.
