Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase.
Brains from subjects who have Alzheimer's disease (AD) express inducible nitric oxide synthase (iNOS). We tested the hypothesis that iNOS contributes to AD pathogenesis. Immunoreactive iNOS was detected in brains of mice with AD-like disease resulting from transgenic expression of mutant human beta-amyloid precursor protein (hAPP) and presenilin-1 (hPS1). We bred hAPP-, hPS1-double transgenic mice to be iNOS(+/+) or iNOS(-/-), and compared them with a congenic WT strain. Deficiency of iNOS substantially protected the AD-like mice from premature mortality, cerebral plaque formation, increased beta-amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of beta-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.
Nathan
Carl
C
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA.
Calingasan
Noel
N
Nezezon
Jon
J
Ding
Aihao
A
Lucia
M Scott
MS
La Perle
Krista
K
Fuortes
Michele
M
Lin
Michael
M
Ehrt
Sabine
S
Kwon
Nyoun Soo
NS
Chen
Junyu
J
Vodovotz
Yoram
Y
Kipiani
Khatuna
K
Beal
M Flint
MF
D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D007178:Inbreeding; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics*
D052247:Nitric Oxide Synthase Type II