Abstract
Our previous study presented evidence that the inflammation-related S100A9 gene is significantly upregulated in the brains of Alzheimer's disease (AD) animal models and human AD patients. In addition, experiments have shown that knockdown of S100A9 expression improves cognition function in AD model mice (Tg2576), and these animals exhibit reduced amyloid plaque burden. In this study, we established a new transgenic animal model of AD by crossbreeding the Tg2576 mouse with the S100A9 knockout (KO) mouse. We observed that S100A9KO/Tg2576 (KO/Tg) mice displayed an increased spatial reference memory in the Morris water maze task and Y-maze task as well as decreased amyloid beta peptide (Aβ) neuropathology because of reduced levels of Aβ, C-terminal fragments of amyloid precursor protein (APP-CT) and phosphorylated tau and increased expression of anti-inflammatory IL-10 and also decreased expression of inflammatory IL-6 and tumor neurosis factor (TNF)-α when compared with age-matched S100A9WT/Tg2576 (WT/Tg) mice. Overall, these results suggest that S100A9 is responsible for the neurodegeneration and cognitive deficits in Tg2576 mice. The mechanism of S100A9 is able to coincide with the inflammatory process. These findings indicate that knockout of S100A9 is a potential target for the pharmacological therapy of AD.
Highlights
The S100 protein family represents the largest sub group within the Ca2+ binding EF-hand superfamily [1]
The S100A9 protein was significantly increased in the cortex and hippocampus of with age-matched S100A9WT/Tg2576 (WT/Tg2576 mice (Tg)) mice brains compared with regionmatched WT/WT mice brains (Figure S1B)
We found that S100A9 levels in S100A9KO/Tg mice brains were decreased compared withS100A9 levels in WT/Tg mice brains
Summary
The S100 protein family represents the largest sub group within the Ca2+ binding EF-hand superfamily [1]. Some S100 proteins, such as S100A6 and S100B, play a prominent role in neurodegenerative disorders, including Alzheimer’s disease (AD) [1,3,4,5,6]. In a recent study on the pro-inflammatory S100A8/A9 proteins, amyloid formation was formed in the aging prostate [7], and our previous study has demonstrated that S100A9 plays a prominent role in AD [8]. S100A9, a the member of the calcium binding S100 protein family that is known as MRP14 or Calgranulin B, is an inflammation-associated protein that is constitutively expressed in neutrophils and inducible in numerous inflammatory cells, including macrophages, epithelial cells, and keratinocytes [9,10,11]. S100A9 plays a role in the inflammation of the AD brain; a detailed mechanism has not been sufficiently reported
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