N-iminoethyl-L-lysine improves memory and reduces amyloid pathology in a transgenic mouse model of amyloid deposition.
A large body of evidence suggests the importance of inflammation and oxidative or nitrosative stress in Alzheimer's disease (AD) pathogenesis. Inflammatory stimuli upregulate transcription of inducible nitric oxide synthase (iNOS), which can lead to the production of nitric oxide and other reactive nitrogen species. We previously found that genetic deletion of iNOS in mice overexpressing the amyloid precursor protein (APP) and presenilin-1 (PS1) reduced mortality, nitrosative stress, amyloid plaque burden, microgliosis, astrocytosis, and peri-plaque tau phosphorylation. We therefore examined the effects of N6-(1-iminoethyl)-L-lysine (L-NIL), a pharmacological iNOS inhibitor, or d-NIL, its enantiomeric control, in a transgenic mouse model of amyloid deposition. Tg19959 mice carry human APP with two mutations and develop amyloid plaques and memory impairment starting at 3-4 months of age. Mice were given L-NIL or D-NIL in the drinking water from 1 month of age and assessed behaviorally and histopathologically at 8 months of age. We found that L-NIL administration reduced disinhibition in the elevated plus maze, improved spatial memory performance in the Morris water maze, and decreased cortical amyloid deposition as well as microglial activation in 8-month-old Tg19959 mice. These findings are consistent with previous reports demonstrating that iNOS inhibition ameliorates AD pathogenesis.
Dumont
Magali
M
Weill Cornell Medical College, Department of Neurology and Neuroscience, New York, NY 10065, USA.
Wille
Elizabeth
E
Calingasan
Noel Y
NY
Nathan
Carl
C
Flint Beal
M
M
Lin
Michael T
MT
D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D016875:tau Proteins; D052247:Nitric Oxide Synthase Type II; D008239:Lysine