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Aging and disease    2018, Vol. 9 Issue (5) : 785-797     DOI: 10.14336/AD.2017.1028
Orginal Article |
The Synergy of Aging and LPS Exposure in a Mouse Model of Parkinson’s Disease
Yong-Fei Zhao1, Qiong Zhang2, Jian-Feng Zhang1, Zhi-Yin Lou3, Hen-Bing Zu1, Zi-Gao Wang1, Wei-Cheng Zeng1, Kai Yao1, Bao-Guo Xiao2,*
1Department of Neurology, Jinshan Hospital, Fudan University, Shanghai, China
2Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
3Department of Neurology, Xinhua Hospital, Medical College, Shanghai Jiaotong University, Shanghai, China
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Abstract  

Aging is an inevitable physiological challenge occurring in organisms over time, and is also the most important risk factor of neurodegenerative diseases. In this study, we observed cellular and molecular changes of different age mice and LPS-induced Parkinson disease (PD) model. The results showed that behavioral performance and dopaminergic (DA) neurons were declined, accompanied by increased expression of pro-inflammatory factors (TLR2, p-NF-kB-p65, IL-1β and TNF-α), as well as pro-oxidative stress factor gp91phox in aged mice compared with young mice. Aging exaggerated inflammatory M1 microglia, and destroyed the balance between oxidation and anti-oxidation. The intranasal LPS instillation induced PD model in both young and aged mice. The poor behavioral performance and the loss of DA neurons as well as TLR2, p-NF-kB-p65, IL-1β, TNF-α, iNOS and gp91phox were further aggravated in LPS-aged mice. Interestingly, the expression of Nrf2 and HO-1 was up-regulated by LPS only in young LPS-PD mice, but not in aged mice. The results indicate that the synergy of aging process and LPS exposure may prominently aggravate the DA neurons loss caused by more serious neuroinflammation and oxidative stress in the brain.

Keywords Aging      Parkinson’s disease      Lipopolysaccharides      neuroinflammation      oxidative stress     
Corresponding Authors: Xiao Bao-Guo   
About author: These authors contributed equally to this work.
Issue Date: 04 July 2017
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Zhao Yong-Fei
Qiong-Zhang
Zhang Jian-Feng
Lou Zhi-Yin
Zu Hen-Bing
Wang Zi-Gao
Zeng Wei-Cheng
Kai-Yao
Xiao Bao-Guo
Cite this article:   
Zhao Yong-Fei,Qiong-Zhang,Zhang Jian-Feng, et al. The Synergy of Aging and LPS Exposure in a Mouse Model of Parkinson’s Disease[J]. Aging and disease, 2018, 9(5): 785-797.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.1028     OR     http://www.aginganddisease.org/EN/Y2018/V9/I5/785
Figure 1.  Behavioral alterations and TH expression and TH neurons in young and aged mice stimulated with or without LPS

10-12-week B6 mice were given with saline (young control group, n=8) or intranasal LPS (young LPS-PD group, n=8) for 2 months. 15-month B6 mice were given with saline (aged control group, n=8) or intranasal LPS (aged LPS-PD group, n=8) for 2 months. A) adhesive remove test (ART), and B) pole test. TH expression in brain was assayed by Western blot. C) Representative bands of TH immunostaining. D) quantitative data of TH immunostaining. TH neurons in SN of brain was assayed by immunohistochemistry. E) Representative images of TH immunohistochemistry. F) quantitative data of TH positive neurons. Quantitative results of behavioral alterations are mean ± SD of 8 mice in each group, and the quantitative results of TH expression are mean ± SEM of 4 mice in each group. *p<0.05, **p<0.01, ***p<0.001.

Figure 2.  TLR2/p-NF-κB/p65 expression and TLR2/p-NF-κB/p65 microglia in brain of young and aged mice stimulated with or without LPS

Mice were dropped into the bilateral nasal cavity with saline or LPS in young or aged mice for 2 months. TLR2/p-NF-κB/p65 expression in brain was assayed by Western blot. A) Representative bands of TLR2 immunostaining. B) Quantitative data of TLR2 immunostaining. TLR2/p-NF-κB/p65 positive microglia in brain was assayed by double immunohistochemistry of TLR2/p-NF-κB/p65 and CD11b. C) Representative images of TLR2 expression on CD11b+ microglia. D) Quantitative data of double positive cells. E) Representative bands of p-NF-κB/p65 immunostaining. F) Quantitative data of p-NF-κB/p65 immunostaining. G) Representative images of p-NF-κB/p65 expression on CD11b+ microglia. H) Quantitative data of double positive cells. Quantitative results are mean ± SEM of 4 mice in each group. *p<0.05, **p<0.01.

Figure 3.  The levels of TNF-α, IL-1β, iNOS/Arg-1 expression, and iNOS/Arg-1 microglia in brain of young and aged mice stimulated with or without LPS

Mice were dropped into the bilateral nasal cavity with saline or LPS in young or aged mice for 2 months. The levels of TNF-α and IL-1β in brain were assayed by ELISA. A) TNF-α; and B) IL-1β expression in brain was assayed by Western blot. C) Representative bands of iNOS immunostaining. D) Quantitative data of iNOS immunostaining. iNOS/Arg-1 positive microglia in brain was assayed by double immunohistochemistry of iNOS/Arg-1 and CD11b. E) Representative images of iNOS expression on CD11b+ microglia. F) Quantitative data of double positive cells. G) Representative bands of Arg-1 immunostaining. H) Quantitative data of Arg-1 immunostaining. I) Representative images of Arg-1 expression on CD11b+ microglia. J) Quantitative data of double positive cells. Quantitative results are mean ± SEM of 4 mice in each group. *p<0.05, **p<0.01.

Figure 4.  Nrf2/HO-1/Gp91phox expression and Nrf2/HO-1/Gp91phox microglia in brain of young and aged mice stimulated with or without LPS

Mice were dropped into the bilateral nasal cavity with saline or LPS in young or aged mice for 2 months. Nrf2/HO-1/Gp91phox expression in brain was assayed by Western blot. A) Representative bands of Nrf2 immunostaining. B) Quantitative data of Nrf2 immunostaining. Nrf2/HO-1/Gp91phox positive microglia in brain was assayed by double immunohistochemistry of Nrf2/HO-1/Gp91phox and CD11b. C) Representative images of Nrf2 expression on CD11b+ microglia. D) Quantitative data of double positive cells. E) Representative bands of HO-1 immunostaining. F) quantitative data of HO-1 immunostaining; G) Representative images of HO-1 expression on CD11b+ microglia. H) Quantitative data of double positive cells; I) Representative bands of gp91phox immunostaining. J) Quantitative data of gp91phox immunostaining. K) Representative images of gp91phox expression on CD11b+ microglia. L) Quantitative data of double positive cells. Quantitative results are mean ± SEM of 4 mice in each group. *p<0.05, **p<0.01, ***p<0.001.

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