The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP.
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.
Colton
Carol A
CA
Division of Neurology, Duke University Medical Center, Durham, NC 27710, USA. glia01@aol.com
Wilcock
Donna M
DM
Wink
David A
DA
Davis
Judianne
J
Van Nostrand
William E
WE
Vitek
Michael P
MP
D000544:Alzheimer Disease / Q000235:genetics / Q000523:psychology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002908:Chronic Disease; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic / Q000502:physiology*; D009154:Mutation; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D052247:Nitric Oxide Synthase Type II