期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 73, 期 8, 页码 752-769出版社
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0000000000000094
关键词
Alzheimer disease; Magnetic resonance spectroscopy; Mouse model; Neuronal loss; NOS2; Tau pathology
资金
- National Institutes of Health National Institute on Aging [AG031124, AG031845]
- Charles River Discovery Research Services Finland
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 A-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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