Application of compounds inhibiting htr3a and its intracellular signaling pathway in the preparation of drugs for treating and/or preventing AD

A technology for intracellular signaling and compounds, applied to compounds that inhibit Htr3a and its intracellular signaling pathways, and the application field of preparing drugs for the treatment and/or prevention of AD

Active Publication Date: 2021-09-03
TONGJI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, there is currently no good solution on how to stop the progression of AD, slow down the development of AD

Method used

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  • Application of compounds inhibiting htr3a and its intracellular signaling pathway in the preparation of drugs for treating and/or preventing AD
  • Application of compounds inhibiting htr3a and its intracellular signaling pathway in the preparation of drugs for treating and/or preventing AD
  • Application of compounds inhibiting htr3a and its intracellular signaling pathway in the preparation of drugs for treating and/or preventing AD

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] The APP / PS1 transgenic AD mice used in this experiment (purchased from the Model Animal Center of Southern University) are widely used AD model mice.

[0067] First, through western blot analysis, it was found that the expression of Htr3a in the cortex and hippocampus of APP / PS1 transgenic AD mice from 1 to 12 months was significantly increased compared with wild-type (WT) mice ( figure 1 ); secondly, with immunofluorescence staining, the result analysis showed that there was a significant increase of Htr3a-positive cells in the cortex of APP / PS1 transgenic AD mice in 10 months, while Htr3a-positive cells could hardly be detected in WT mice ( figure 2 ).

[0068] It can be seen that the expression level of Htr3a in APP / PS1 transgenic AD mice from 1 to 12 months is significantly higher than that of wild-type mice of the same age.

[0069] Wherein, in the present embodiment, the concrete method of western blot analysis is as follows:

[0070] Littermates of APP / PS1 AD ...

Embodiment 2

[0074] Silencing Htr3a in APP / PS1 AD mice, and reducing Htr3a observed the effect on amyloid plaques in APP / PS1 AD mice.

[0075] AAV-htr3a shRNA-GFP virus was prepared, and AAV-EGFP empty virus was used as control. Six-and-a-half-month-old WT mice and APP / PS1 AD mice were injected bilaterally into the hippocampus. The experiment was divided into three groups: (1) WT mice were given the same volume of AAV-EGFP (CON-AAV); (2) APP / PS1 AD mice were given AAV-EGFP (CON-AAV, titer 2.19×10 9 V.G / each side; (3) APP / PS1AD mice were given AAV-Htr3a shRNA-GFP virus (titer: 2.19×10 9 V.G / each side). After the injection, the animals were fed for 4 weeks, overly anesthetized, and the brain tissue was taken for western blot protein hybridization experiment and immunofluorescence staining. Refer to Example 1 for the methods of western blot protein hybridization experiment and immunofluorescence staining.

[0076] Protein hybridization experiments showed that in the Htr3a shRNA-AAV virus i...

Embodiment 3

[0078] Study on whether reducing the expression of Htr3a in APP / PS1 AD mice has any effect on Aβ amyloid

[0079] In order to study whether reducing the expression of Htr3a in APP / PS1 AD mice has an impact on Aβ amyloid, in this embodiment, immunofluorescent staining for Aβ amyloid ( Figure 5 ) and western blot ( Figure 6 ) analysis and thioflavin staining of Aβ amyloid ( Figure 7 ), for the analysis of Aβ amyloid plaques.

[0080] The results showed that Htr3a and Aβ amyloid plaques of APP / PS1 AD mice were significantly reduced compared with AD mice (administered with empty virus).

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Abstract

The present invention relates to the application of compounds inhibiting Htr3a and its downstream intracellular signaling pathways in the preparation of medicines for treating and / or preventing Alzheimer's disease. The present invention finds for the first time that the expression of Htr3a in Alzheimer's disease transgenic AD animals and AD patients is significantly increased, and the intracellular calcium (Ca 2+ ) and its downstream calcineurin activity (CaN) and transcription factor (NFAT) were significantly increased. In AD transgenic mice, inhibiting the function of Htr3a significantly reduces the production of Aβ-amyloid protein and reverses the intracellular signaling pathway Ca 2+ , CaN, and the transcription factor NFAT inhibited glial cell activation and reduced neuroinflammation. The present invention considers for the first time that Htr3a and its intracellular signaling pathway play an important role in the generation of β-amyloid plaques in AD, and regulating this pathway can prevent the progressive development of AD. Therefore, drugs targeting this pathway can prevent the process of AD, slow down the development of AD, and have great research and application prospects in the treatment of AD.

Description

technical field [0001] The invention relates to the technical field of drug research for treating or preventing Alzheimer's disease, in particular to the application of a compound inhibiting Htr3a and its intracellular signaling pathway in the preparation of drugs for treating and / or preventing AD. Background technique [0002] Alzheimer's disease is a degenerative disease of the central nervous system characterized by progressive cognitive dysfunction and behavioral impairment. According to the 2015 World Alzheimer Report, there are about 46.8 million Alzheimer's patients in the world, with an average of one new case every 3 seconds. Currently, there are more than 8 million Alzheimer's patients in my country. The prevalence of Alzheimer's disease is 5% among people over the age of 65; the prevalence increases to 25% over the age of 85, and as high as 60% for the elderly over the age of 95. Due to the aging population, AD patients bring huge mental and economic burdens to ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61P25/28G01N33/68
CPCA61K45/00A61P25/28G01N33/68G01N2333/705G01N2500/00G01N2800/2821
Inventor 袁琼兰
Owner TONGJI UNIV
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