Chinese Medical Sciences Journal ›› 2022, Vol. 37 ›› Issue (4): 320-330.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
Ran Li1, Zhanyun Lv2, Yanxin Li3, Wei Li4, Yanlei Hao4, *(
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- 1School of Basic Medical Sciences, Shandong University, Jinan 250012, China
2Zhejiang University Medical Center, Hangzhou 311121, China
3Department of Neurology, Pingdu People’s Hospital, Qingdao, Shandong 266799, China
4Department of Neurology, Affiliated Hospital of Jining Medical College, Jining, Shandong 272007, China
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Received:2022-01-06Accepted:2022-04-02Published:2022-12-31Online:2022-09-29 -
Contact:Yanlei Hao E-mail:yanleihao301@live.com
Cite this article
Ran Li, Zhanyun Lv, Yanxin Li, Wei Li, Yanlei Hao. 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.
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Figure 1.
Sequencing peaks of TYROBP knockout mice, AD mice with PSEN1 p.G???E knockin and hybrid mice. A-C: The sequencing peaks of TYROBP gene knockout mice; A. WT, B. heterozygous type (Tyrobp+/-), C. homozygous type (Tyrobp-/-). D-F: The sequencing peaks of AD mice knocked in PSEN1 p.G???E; D. WT, E. heterozygous type (PSEN1G378E/WT), F. homozygous type (PSEN1G378E/G378E). G-I: The sequencing peaks of hybrid mice; G. WT, H. heterozygous type (PSEN1G378E/WT; Tyrobp+/-), I. homozygous type (PSEN1G378E/G378E; Tyrobp-/-). The arrows indicate the positions of gene knock-in. TYROBP: TYRO protein kinase-binding protein; AD: Alzheimer’s disease; PSEN1: presenilin 1; WT: wild type."
Figure 1.
Figure 2.
TYROBP deficiency improved learning ability of PSEN1 p.G???E knockin early-onset AD mouse models. (A-E) Expression of TYROBP in the hippocampus of the early-onset AD models. (A) immunofluorescence results of hippocampal sections to detect IBA1-positive microglia and the TYROBP expressing cells in hippocampus; (B) representative western blots of hippocampal lysate; (C-E) semi-quantitative analysis results of western blots, **P < 0.01 (n=4). (F-H) Results of the hidden platform test in the Morris water maze, during which escape latency (defined as the time taken to find the platform) was measured on the 5th day of training, *P < 0.05 (n = 8). (I) Swimming trajectories in the hidden platform test on day 1 and 5 day of training. IBA1: ionized calcium binding adapter molecule-1."
Figure 2.
Table 1.
The latency of escape of the AD mouse models (mean ± SD, s, n = 8)"
| Groups | Day1 | Day2 | Day3 | Day4 | Day5 |
|---|---|---|---|---|---|
| WT | 46.51 ± 17.29 | 42.40 ± 11.79 | 27.55 ± 12.73 | 13.81 ± 9.78 | 6.21 ± 3.89 |
| Tyrobp+/- | 58.69 ± 3.71 | 47.48 ± 17.69 | 35.69 ± 20.93 | 30.59 ± 19.32 | 17.27 ± 6.89** |
| Tyrobp-/- | 54.33 ± 16.05 | 46.53 ± 19.59 | 44.55 ± 16.91 | 19.34 ± 13.30 | 14.83 ± 12.72+ |
| PSEN1G378E/WT | 60.00 ± 0.00 | 54.79 ± 9.65 | 47.24 ± 18.64* | 32.71 ± 26.63 | 32.66 ± 17.24** |
| PSEN1G378E/G378E | 60.00 ± 0.00 | 57.48 ± 7.14 | 54.75 ± 9.78** | 41.98 ± 14.52* | 34.90 ± 17.25*** |
| PSEN1G378E/WT; Tyrobp+/- | 57.25 ± 7.77 | 47.15 ± 15.89 | 39.04 ± 20.72 | 22.29 ± 18.91 | 13.04 ± 8.66# |
| PSEN1G378E/G378E; Tyrobp-/- | 56.15 ± 10.89 | 46.38 ± 21.10 | 40.46 ± 18.86 | 21.35 ± 11.87 | 9.31 ± 5.27+ |
Table 1.
Figure 3.
Levels of total and (hyper)phosphorylated Tau in the hippocampus of PSEN1 p.G???E knockin AD mouse models in the presence or absence of TYROBP. (A) Representative western blots of hippocampal lysate. (B-D) Semi-quantitative results of expression levels of the following proteins: total Tau (Tau5), phosphorylated Tau (pTau), pSer202/Thr205 (AT8), p-Tau T181(pT181), p-Tau T231(pT231), p-Tau pSer396/pSer404 (PHF1). *P < 0.05, **P < 0.01, (n = 4). PHF-1: plant homeodomain finger protein 1: GAPDH: glycera dehyde-3-phosphate dehydrogenase."
Figure 3.
Figure 4.
Activity of tau kinases in the hippocampus of AD mouse models in the presence or absence of TYROBP analyzed with Western blotting. (A) Representative western blots of hippocampal lysate. (B-D) The ratios of phosphorylated to total protein for CDK5, ERK and GSK3. *P < 0.05, **P < 0.01 (n = 4). CDK5: cyclin dependent kinase 5; p-CDK5: phosphorylated CDK5; ERK: extracellular regulated protein kinases; p-ERK: phosphorylated ERK; GSK3: glycogen synthase kinase 3; p-GSK3: phosphorylated GSK3."
Figure 4.
Figure 5.
Number of microglia and astrocytes in the brains of AD mice at presence or absence of TYROBP detected using immunofluorescence and Western blotting. (A) Immunofluorescence analysis of hippocampal sections to detect IBA1-positive microglia and GFAP-positive astrocytes in hippocampus (scale bar, 200 μm). (B) Representative western blots of hippocampal lysates. (C-E) Semi-quantitative results of the target proteins. *P < 0.05, **P < 0.01 (n = 4). GFAP: glial fibrillary acidic protein."
Figure 5.
Figure 6.
IL-6, IL-1β and TNF-α levels in the hippocampal lysate of AD mice in the presence or absence of TYROBP detected by ELISA. *P < 0.05, **P < 0.01 (n = 3). IL-6: interleukin-6; IL-1β: interleukin-1β; TNF-α: tumor necrosis factor-α."
Figure 6.
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