Beta-amyloid plaques induce neuritic dystrophy of nitric oxide-producing neurons in a transgenic mouse model of Alzheimer's disease.
A causative role for nitric oxide has been postulated in a number of neurodegenerative diseases. Using histochemical and immunohistochemical methods, we examined the effect of beta-amyloid plaques on nitric oxide-producing cells in transgenic mice which overexpress a mutant human amyloid precursor protein (APP). In 14-month-old animals, nitric oxide synthase (NOS)-positive dystrophic neurites were observed frequently in the cerebral cortex and hippocampus of all of 16 plaque-bearing transgenic animals and in none of 16 wild-type animals. Double labeling of NOS and beta-amyloid revealed that 90% of beta-amyloid plaques were associated with NOS-containing dystrophic neurites. In 7-month-old animals, beta-amyloid plaques were very rare, but those present were frequently associated with NOS-positive neuritic dystrophy. We conclude that beta-amyloid plaques induce neuritic dystrophy in cortical neurons containing NOS in this model of AD, and hypothesize that this finding may be relevant to the mechanism of beta-amyloid neurotoxicity in human AD.
Quinn
J
J
Portland Veteran's Affairs Medical Center, P3 R&D, 3710 SW US Veteran's Hospital Road, Portland, Oregon 97201, USA. quinnj@ohsu.edu
Davis
F
F
Woodward
W R
WR
Eckenstein
F
F
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D019150:Neuroaxonal Dystrophies / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology
D016229:Amyloid beta-Peptides; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse