MNos2 deletion and human NOS2 replacement in alzheimer disease models

Carol A. Colton, Joan G. Wilson, Angela Everhart, Donna M. Wilcock, Jukka Puoliväli, Taneli Heikkinen, Juho Oksman, Olli Jääskeläinen, Kimmo Lehtimäki, Teemu Laitinen, Nina Vartiainen, Michael P. Vitek

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Pages (from-to)752-769
Number of pages18
JournalJournal of Neuropathology and Experimental Neurology
Volume73
Issue number8
DOIs
StatePublished - Aug 2014

Keywords

  • Alzheimer disease
  • Magnetic resonance spectroscopy
  • Mouse model
  • NOS2
  • Neuronal loss
  • Tau pathology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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