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mNos2 deletion and human NOS2 replacement in Alzheimer disease models.

Publication ,  Journal Article
Colton, CA; Wilson, JG; Everhart, A; Wilcock, DM; Puoliväli, J; Heikkinen, T; Oksman, J; Jääskeläinen, O; Lehtimäki, K; Laitinen, T; Vitek, MP ...
Published in: J Neuropathol Exp Neurol
August 2014

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.

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Published In

J Neuropathol Exp Neurol

DOI

EISSN

1554-6578

Publication Date

August 2014

Volume

73

Issue

8

Start / End Page

752 / 769

Location

England

Related Subject Headings

  • Phosphorylation
  • Nitric Oxide Synthase Type II
  • Neurology & Neurosurgery
  • Neurodegenerative Diseases
  • Mutation
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Maze Learning
  • Male
 

Citation

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Colton, C. A., Wilson, J. G., Everhart, A., Wilcock, D. M., Puoliväli, J., Heikkinen, T., … Vitek, M. P. (2014). mNos2 deletion and human NOS2 replacement in Alzheimer disease models. J Neuropathol Exp Neurol, 73(8), 752–769. https://doi.org/10.1097/NEN.0000000000000094
Colton, Carol A., Joan G. Wilson, Angela Everhart, Donna M. Wilcock, Jukka Puoliväli, Taneli Heikkinen, Juho Oksman, et al. “mNos2 deletion and human NOS2 replacement in Alzheimer disease models.J Neuropathol Exp Neurol 73, no. 8 (August 2014): 752–69. https://doi.org/10.1097/NEN.0000000000000094.
Colton CA, Wilson JG, Everhart A, Wilcock DM, Puoliväli J, Heikkinen T, et al. mNos2 deletion and human NOS2 replacement in Alzheimer disease models. J Neuropathol Exp Neurol. 2014 Aug;73(8):752–69.
Colton, Carol A., et al. “mNos2 deletion and human NOS2 replacement in Alzheimer disease models.J Neuropathol Exp Neurol, vol. 73, no. 8, Aug. 2014, pp. 752–69. Pubmed, doi:10.1097/NEN.0000000000000094.
Colton CA, Wilson JG, Everhart A, Wilcock DM, Puoliväli J, Heikkinen T, Oksman J, Jääskeläinen O, Lehtimäki K, Laitinen T, Vartiainen N, Vitek MP. mNos2 deletion and human NOS2 replacement in Alzheimer disease models. J Neuropathol Exp Neurol. 2014 Aug;73(8):752–769.
Journal cover image

Published In

J Neuropathol Exp Neurol

DOI

EISSN

1554-6578

Publication Date

August 2014

Volume

73

Issue

8

Start / End Page

752 / 769

Location

England

Related Subject Headings

  • Phosphorylation
  • Nitric Oxide Synthase Type II
  • Neurology & Neurosurgery
  • Neurodegenerative Diseases
  • Mutation
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Maze Learning
  • Male