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mNos2 deletion and human NOS2 replacement in Alzheimer disease models.
J Neuropathol Exp Neurol. 2014 Aug; 73(8):752-69.JN

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+Show Affiliations

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).No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25003233

Citation

Colton, Carol A., et al. "MNos2 Deletion and Human NOS2 Replacement in Alzheimer Disease Models." Journal of Neuropathology and Experimental Neurology, vol. 73, no. 8, 2014, pp. 752-69.
Colton CA, Wilson JG, Everhart A, et al. MNos2 deletion and human NOS2 replacement in Alzheimer disease models. J Neuropathol Exp Neurol. 2014;73(8):752-69.
Colton, C. A., Wilson, J. G., Everhart, A., Wilcock, D. M., Puoliväli, J., Heikkinen, T., Oksman, J., Jääskeläinen, O., Lehtimäki, K., Laitinen, T., Vartiainen, N., & Vitek, M. P. (2014). MNos2 deletion and human NOS2 replacement in Alzheimer disease models. Journal of Neuropathology and Experimental Neurology, 73(8), 752-69. https://doi.org/10.1097/NEN.0000000000000094
Colton CA, et al. MNos2 Deletion and Human NOS2 Replacement in Alzheimer Disease Models. J Neuropathol Exp Neurol. 2014;73(8):752-69. PubMed PMID: 25003233.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - mNos2 deletion and human NOS2 replacement in Alzheimer disease models. AU - Colton,Carol A, AU - Wilson,Joan G, AU - Everhart,Angela, AU - Wilcock,Donna M, AU - Puoliväli,Jukka, AU - Heikkinen,Taneli, AU - Oksman,Juho, AU - Jääskeläinen,Olli, AU - Lehtimäki,Kimmo, AU - Laitinen,Teemu, AU - Vartiainen,Nina, AU - Vitek,Michael P, PY - 2014/7/9/entrez PY - 2014/7/9/pubmed PY - 2014/9/3/medline SP - 752 EP - 69 JF - Journal of neuropathology and experimental neurology JO - J. Neuropathol. Exp. Neurol. VL - 73 IS - 8 N2 - 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. SN - 1554-6578 UR - https://www.unboundmedicine.com/medline/citation/25003233/mNos2_deletion_and_human_NOS2_replacement_in_Alzheimer_disease_models_ L2 - https://academic.oup.com/jnen/article-lookup/doi/10.1097/NEN.0000000000000094 DB - PRIME DP - Unbound Medicine ER -