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Application of CD4+T cell-derived BACE1, EP2 and EP4 as Alzheimer disease treatment target

A technology for Alzheimer's disease, cells, applied in the field of biomedicine

Pending Publication Date: 2021-07-09
UNIV OF SCI & TECH OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] So far, no research results have confirmed that CD4 + T cell-derived BACE1 and / or EP2 and / or EP4 can be used as therapeutic targets for AD, and looking for a way to selectively regulate CD4 + Drugs of T cell-derived BACE1 and / or EP2 and / or EP4 genes or proteins are of great significance for the treatment of AD

Method used

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  • Application of CD4+T cell-derived BACE1, EP2 and EP4 as Alzheimer disease treatment target
  • Application of CD4+T cell-derived BACE1, EP2 and EP4 as Alzheimer disease treatment target
  • Application of CD4+T cell-derived BACE1, EP2 and EP4 as Alzheimer disease treatment target

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1 BACE1 specifically cleaves the precursor form of mPGES2

[0080] 1. Experimental process

[0081] In order to confirm the relationship between BACE1 and mPGES2, the present invention constructs HEK293 cells stably transfected with HA-BACE1 and Flag-mPGES2 plasmids, and detects the precursor form of mPGES2 (molecular weight is 43kDa) by Western blotting (Western blot) technique and mature form (molecular weight of 34kDa) (attached figure 1 ). At the same time, in order to confirm that the regulation of BACE1 on mPGES2 is specific, we also constructed another prostaglandin synthase mPGES1 (GFP-mPGES1 plasmid) and HEK293 cells stably expressing the BACE1 plasmid, and also carried out Western blot detection (attached figure 1 ). On the other hand, the present invention utilizes siRNA and CRISPR-Cas9 technology to construct stable BACE1 knockdown (knockdown) and knockout (KO, knockout) cell lines, transfect Flag-mPGES2 plasmid in this cell line, use Western blot...

Embodiment 2

[0113] Example 2 CD4 + T cell-derived BACE1 also cleaves the mPGES2 precursor form, thereby regulating the PGE2 signaling pathway

[0114] 1. Experimental process

[0115] To explore CD4 + Whether T cell-derived BACE 1 (under different physiological conditions or in different cells, BACE1 may have different selectivity for substrate cleavage) can also cleavage the precursor form of mPGES2, the present invention utilizes BACE1 knockout Mice BACE 1 - / - Mice and BACE1 overexpressing mice are HUBC mice. Through magnetic bead sorting technology, the present invention will BACE 1 - / - CD4 of mice and HUBC mice + T cells were isolated, and the expression of BACE1 was detected by Western blot (attached Figure 4 And attached Figure 5 ). Experiments of the present invention confirm that CD4 + T cell-derived BACE1 can cleave the precursor form of mPGES2, and BIV, an inhibitor of BACE1, can significantly inhibit this cleaving (attached Image 6 ). Further experiments of the pr...

Embodiment 3

[0168] Example 3 BACE1 regulates CD4 through PGE2 + T cell TCR pathway activation

[0169] 1. Experimental process

[0170] To explore whether BACE1 regulates CD4 + T function, the present invention confirms that PGE2 can promote CD4 + Activation of the TCR pathway and its downstream pathways in T cells (attached Figure 14 ), and knockdown of BACE1 can significantly inhibit CD4 + Activation of the TCR pathway in T cells (attached Figure 15 ), on the contrary, overexpression of BACE1 can promote CD4 + Activation of the TCR pathway in T cells (attached Figure 16 ).

[0171] 2. Experimental materials

[0172] BACE 1 - / - Mice were purchased from Jackson Laboratories; HUBC mice were commissioned to construct by Tongji University; cell sorting reagent Anti-PE beads (130-048-801, Miltenyi Biotec); Ultra-LEAF TM Purified anti-mouse CD28(102115) and Ultra-LEAF TM Purified anti-mouse CD3 (100340) was purchased from Bioledgend; 20× phosphate buffered saline (20×PBS, the ...

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Abstract

The invention belongs to the technical field of biological medicine and relates to application of CD4+ T cell-derived BACE1 and / or prostaglandin E2 receptor EP2 and / or EP4 as a therapeutic target of Alzheimer's disease. It is found for the first time that CD4 + T cell-derived BACE1 can specifically shear prostaglandin synthetase precursor protein mPGES2, so that the maturation of mPGES2 is promoted, synthesis of prostaglandin PGE2 is promoted through mature mPGES2, and therefore, abnormal activation of CD4 + T cells is caused; meanwhile, the CD4 + T cells are abnormally activated and the expression of BACE1 is increased in AD patient and AD mouse models; meanwhile, the PGE2 receptor EP2 / EP4 antagonist can improve the pathological phenotype of the Alzheimer's disease. Therefore, the CD4 + T cell-derived BACE1 and / or EP2 and / or EP4 can be used as a target for treating the Alzheimer's disease, and a new target is provided for researching a novel medicine for treating the Alzheimer's disease.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to CD4 + Use of T cell-derived BACE1 and / or EP2 and / or EP4 as a therapeutic target for Alzheimer's disease. Background technique [0002] Alzheimer's disease (AD) is the most common neurodegenerative disease and the most important type of dementia, mainly manifested as cognitive and memory dysfunction. Although there is increasing evidence that AD pathology begins to deposit in the brain from middle age, clinical pathological symptoms generally occur after the age of 65. With the increasing aging of the global population, the proportion of the population aged 65 has increased significantly, leading to a rapid increase in the incidence of AD. Epidemiological research predicts that from 1997 to 2050, the elderly population over 65 years old will grow globally, of which the Americas will grow from 63 million to 137 million, Africa will grow from 18 million to 380 million, and Eur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K48/00A61K31/713A61K31/166A61K31/397A61K31/443A61P25/28G01N33/68
CPCA61K45/00A61K31/713A61K31/166A61K31/397A61K31/443A61P25/28G01N33/6896G01N2800/2821
Inventor 申勇戴林斌
Owner UNIV OF SCI & TECH OF CHINA
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