Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer’s Disease Mouse Model Carrying a <italic style="font-style: italic">PSEN1</italic> p.G378E Mutation

Ran Li; Zhanyun Lv; Yanxin Li; Wei Li; Yanlei Hao

doi:10.24920/004059

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Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer’s Disease Mouse Model Carrying a PSEN1 p.G378E Mutation

Chinese Medical Sciences Journal Vol. 37, Issue 4, Pages: 320-330(2022)

Original article | Updated：2024-04-10

- Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer’s Disease Mouse Model Carrying a PSEN1 p.G378E Mutation
- Affiliations：
  
  1. 1School of Basic Medical Sciences, Shandong University, Jinan 250012, China
  2. 2Zhejiang University Medical Center, Hangzhou 311121, China
  3. 3Department of Neurology, Pingdu People’s Hospital, Qingdao, Shandong 266799, China
  4. 4Department of Neurology, Affiliated Hospital of Jining Medical College, Jining, Shandong 272007, China
- Author bio：
  
  * yanleihao301@live.com
- Funds：
- DOI：10.24920/004059
  CLC：
- Received：06 January 2022，
  
  Accepted：2022-4-2，
  
  Published Online：29 September 2022，
  
  Published：31 December 2022
- Accepted：
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Ran Li, Zhanyun Lv, Yanxin Li, et al. Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer’s Disease Mouse Model Carrying a PSEN1 p.G378E Mutation[J]. Chinese medical sciences journal, 2022, 37(4): 320-330.
DOI：

Ran Li, Zhanyun Lv, Yanxin Li, et al. Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer’s Disease Mouse Model Carrying a PSEN1 p.G378E Mutation[J]. Chinese medical sciences journal, 2022, 37(4): 320-330. DOI： 10.24920/004059.

摘要

目的

研究酪氨酸蛋白激酶结合蛋白（TYRO protein kinase-binding protein，TYROBP）缺乏对携带

PSEN1

p.G378E突变的新型阿尔茨海默病（Alzheimer’s disease，AD）小鼠模型的学习行为、胶质细胞活化、促炎因子以及Tau磷酸化的影响。

方法

我们基于前期发现的一个携带

PSEN1

突变的AD家族，构建了一种携带

PSEN1

p.G378E突变的新型AD小鼠模型，与TYROBP缺乏小鼠杂交红后获得杂合子小鼠（

PSEN1

G378E/WT

；

Tyrobp

+/-

）和纯合子小鼠（

PSEN1

G378E/G378E

；

Tyrobp

）。采用水迷宫实验检测小鼠的空间学习和记忆能力；处死小鼠后摘取海马用于进一步分析。采用免疫荧光法检测TYROBP的表达及小胶质细胞和星形胶质细胞的数量，采用免疫印迹法检测Tau蛋白和磷酸化Tau蛋白的表达水平，采用酶联免疫吸附测定检测促炎因子的水平。

结果

小鼠海马小胶质细胞特异性表达TYROBP。TYROBP缺乏能防止

PSEN1

G378E

突变小鼠模型学习行为的恶化，同时降低海马胶质细胞和星形胶质细胞的数量以及白细胞介素-6，白细胞介素-1

和肿瘤坏死因子-

的水平（

0.05）。与

PSEN1

G378E/G378E

小鼠相比，

PSEN1

G378E/G378E

；

Tyrobp

-/-

小鼠的AT8/Tau5、PHF1/Tau5、pT181/Tau5、pT231/Tau5、p-ERK/ERK比值均较高（

0.05）。

结论

TYROBP缺乏可能对AD小鼠模型的神经炎症过程具有保护作用。然而，包括小胶质细胞和星形胶质细胞激活以及促炎因子释放在内的神经炎症过程与磷酸化Tau之间的关系还需进一步研究。

Abstract

Objective

To study the effects of TYRO protein kinase-binding protein (TYROBP) deficiency on learning behavior

glia activation and pro-inflammatory cycokines

and Tau phosphorylation of a new Alzheimer’s disease (AD) mouse model carrying a

PSEN1

p.G378E mutation.

Methods

A new AD mouse model carrying

PSEN1

p.G378E mutation was built based on our previously found AD family which might be ascribed to the

PSEN1

mutation

and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice (

PSEN1

G378E/WT

;

Tyrobp

+/-

) and the homozygous hybrid mice (

PSEN1

G378E/G378E

;

Tyrobp

-/-

). Water maze test was used to detect spatial learning and memory ability of mice. After the mice were sacrificed

the hippocampus was excised for further analysis. Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte. Western blot was used to detect the expression levels of Tau and phosphorylated Tau (p-Tau)

and ELISA to measure the levels of pro-inflammatory cytokines.

Results

Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus. Absence of TYROBP in

PSEN1

G378E

mutation mouse model prevented the deterioration of learning behavior

decreased the numbers of microglia and astrocytes

and the levels of interleukin-6

interleukin-1β and tumor necrosis factor-

in the hippocampus (all

0.05). The ratios of AT8/Tau5

PHF1/Tau5

pT181/Tau5

pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice (

PSEN1

G378E/G378E

;

Tyrobp

-/-

mice) compared with

PSEN1

G378E/G378E

mice (all

0.05).

Conclusions

TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD. However

the relationship between neuroinflammation processes involving microglia and astrocyte activation

and release of pro-inflammatory cytokines

and p-Tau pathology needs further study.

关键词

Keywords

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⁰

Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer’s Disease Mouse Model Carrying a PSEN1 p.G378E Mutation

DOI：10.24920/004059

摘要

Abstract

关键词

Keywords

references