title: mNos2 deletion and human NOS2 replacement in Alzheimer disease models.
abstract: Understanding the pathophysiologic mechanisms underlying Alzheimer disease relies on knowledge of disease onset and the sequence of development of brain pathologies. We present a comprehensive analysis of early and progressive changes in a mouse model that demonstrates a full spectrum of characteristic Alzheimer disease-like pathologies. This model demonstrates an altered immune redox state reminiscent of the human disease and capitalizes on data indicating critical differences between human and mouse immune responses, particularly in nitric oxide levels produced by immune activation of the NOS2 gene. Using the APPSwDI(+)/(+)mNos2(-/-) (CVN-AD) mouse strain, we show a sequence of pathologic events leading to neurodegeneration,which include pathologically hyperphosphorylated tau in the perforant pathway at 6 weeks of age progressing to insoluble tau, early appearance of β-amyloid peptides in perivascular deposits around blood vessels in brain regions known to be vulnerable to Alzheimer disease, and progression to damage and overt loss in select vulnerable neuronal populations in these regions. The role of species differences between hNOS2 and mNos2 was supported by generating mice in which the human NOS2 gene replaced mNos2. When crossed with CVN-AD mice, pathologic characteristics of this new strain (APPSwDI(+)/(-)/HuNOS2(tg+)/(+)/mNos2(-/-)) mimicked the pathologic phenotypes found in the CVN-AD strain.
authors.affiliation: From the Department of Neurology, Duke University Medical Center, Durham, North Carolina (CAC, JGW, AE, DMW, MPV); and Charles River Discovery Research Services Finland, Kuopio, Finland (JP, TH, JO, OJ, KL, TL, NV).
authors.forename: Carol A
authors.initials: CA
authors.lastname: Colton
authors.forename: Joan G
authors.initials: JG
authors.lastname: Wilson
authors.forename: Angela
authors.initials: A
authors.lastname: Everhart
authors.forename: Donna M
authors.initials: DM
authors.lastname: Wilcock
authors.forename: Jukka
authors.initials: J
authors.lastname: Puoliväli
authors.forename: Taneli
authors.initials: T
authors.lastname: Heikkinen
authors.forename: Juho
authors.initials: J
authors.lastname: Oksman
authors.forename: Olli
authors.initials: O
authors.lastname: Jääskeläinen
authors.forename: Kimmo
authors.initials: K
authors.lastname: Lehtimäki
authors.forename: Teemu
authors.initials: T
authors.lastname: Laitinen
authors.forename: Nina
authors.initials: N
authors.lastname: Vartiainen
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003214:Conditioning, Classical / Q000502:physiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse