Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase

• Published in: The Journal of experimental medicine Vol. 202; no. 9; pp. 1163 - 1169
• Main Authors: Nathan, Carl, Calingasan, Noel, Nezezon, Jon, Ding, Aihao, Lucia, M. Scott, La Perle, Krista, Fuortes, Michele, Lin, Michael, Ehrt, Sabine, Kwon, Nyoun Soo, Chen, Junyu, Vodovotz, Yoram, Kipiani, Khatuna, Beal, M. Flint
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 07.11.2005
• Subjects: Alzheimer Disease - enzymology; Alzheimer Disease - genetics; Alzheimer Disease - mortality; Alzheimer Disease - pathology; Animals; Brain - enzymology; Brain - pathology; Brief Definitive Report; Crosses, Genetic; Disease Models, Animal; Gene Deletion; Humans; Inbreeding; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nitric Oxide Synthase Type II - deficiency; Nitric Oxide Synthase Type II - genetics
• ISSN: 0022-1007; 1540-9538; 1892-1007
• DOI: 10.1084/jem.20051529

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 β-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 β-amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of β-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.