TITLE:
Absence of Nitric Oxide Synthase 3 Increases Amyloid β-Protein Pathology in Tg-5xFAD Mice
AUTHORS:
Zishuo Ian Hu, Ann Marie E. Kotarba, William E. Van Nostrand
KEYWORDS:
Nitric Oxide Synthase 3; Amyloid β-Protein, Alzheimer’s Disease; Transgenic Mice; Deposition
JOURNAL NAME:
Neuroscience and Medicine,
Vol.4 No.2,
June
18,
2013
ABSTRACT: Aim: The
abnormal accumulation, assembly and deposition of the amyloid β-protein (Aβ) are prominent pathological features of patients with Alzheimer’s
disease (AD) and related disorders. A number of factors in the brain can
influence Aβ accumulation and
associated pathologies. The aim of the present study was to determine the
consequences of deleting
nitric oxide synthase (NOS) 3, the endothelial form of NOS, in Tg-5xFAD mice, a
model of parenchymal AD-like amyloid pathology. Methods: Tg-5xFAD mice were bred with NOS3-/- mice.
Cohorts of Tg-5xFAD mice and bigenic Tg-5xFAD/NOS3-/- mice were aged
to six months followed by collection of the blood and brain tissues from the
mice for biochemical and pathological analyses. Results: ELISA analyses show that the absence of NOS3 results in
elevated levels of cerebral and plasma Aβ peptides in Tg-5xFAD mice. Immunohistochemical analyses show that the absence
of NOS3 increased the amount of parenchymal Aβ deposition and fibrillar amyloid accumulation in Tg-5xFAD mice.
The elevated levels of Aβ were not
due to changes in the expression levels of transgene encoded human amyloid
precursor protein (APP), endogenous β-secretase,
or increased proteolytic processing of APP. Conclusions: The results from this study suggest that the loss of
NOS3 activity enhances Aβ pathology
in Tg-5xFAD mice. These findings are similar to previous studies of NOS2
deletion suggesting that reduced NOS activity and NO levels enhance amyloid-associated
pathologies in human APP transgenic mice.