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Application of the substance reducing the combination of β-arrestin 1 and aph-1 protein in the preparation of drugs for preventing and treating neurodegenerative diseases

A neurodegenerative and inhibitory protein technology, applied in the direction of nervous system diseases, peptide/protein components, applications, etc., can solve problems such as the unclear role of β-Arrestin1

Active Publication Date: 2018-01-02
CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the role of β-Arrestin1 in the physiology and pathology of the central nervous system is not clear

Method used

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  • Application of the substance reducing the combination of β-arrestin 1 and aph-1 protein in the preparation of drugs for preventing and treating neurodegenerative diseases
  • Application of the substance reducing the combination of β-arrestin 1 and aph-1 protein in the preparation of drugs for preventing and treating neurodegenerative diseases
  • Application of the substance reducing the combination of β-arrestin 1 and aph-1 protein in the preparation of drugs for preventing and treating neurodegenerative diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0237] Example 1. Increased expression levels of β-Arrestin in Alzheimer's disease humans and transgenic model mice

[0238] First, in order to investigate whether β-Arrestin is altered in Alzheimer's disease, the inventors detected the expression level of β-Arrestin in brain samples of patients. Patient samples were evaluated according to the Braak staging method dependent on neuropathological indicators, and were divided into 7 groups according to the degree of lesion (Braak 0, I, II, III, IV and VI stages in turn) [Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta. Neuropathol. 82(4), 239-259 (1991)]. like figure 1 and figure 2As shown, the expression of β-Arrestin was detected by Western hybridization, and it was found that the protein level of β-Arrestin1 was positively correlated with Braak stage (r=0.725, Pfigure 1 and image 3 As shown, the expression level of β-Arrestin2 was also positively correlated with Braak stage (r=0.508, P<...

Embodiment 2

[0252] Example 2. β-Arrestin1 regulates γ-secretase activity by binding to APH-1AL

[0253] The inventor's previous research found that activated β2AR can enhance its protease activity by mediating γ-secretase into the endocytic pathway. In order to test whether endocytosis is involved in the regulation of β-Arrestin1 on γ-secretase, the inventors used dominant negative mutants of Rab5 and Rab7 (Rab5S34N and Rab7T22N) that regulate the formation of endocytic transport vesicles to inhibit endocytosis translocation process, and found that neither Rab5S34N nor Rab7T22N could inhibit the γ-secretase activity enhanced by β-Arrestin1 ( Figure 17 ). Therefore, the possibility that endocytosis is involved in the regulation of β-Arrestin1 on γ-secretase is ruled out.

[0254] β-Arrestin1 can regulate different signaling pathways by binding to cell surface receptors and intracellular signaling pathway molecules. The inventors speculate that protein-protein interaction may be involve...

Embodiment 3

[0264] Example 3. β-Arrestin1 regulates the assembly of γ-secretase complex

[0265] APH-1AL is a scaffold protein in the assembly process of the γ-secretase complex, which is necessary for the formation of a stable and active γ-secretase multiprotein large molecular weight complex [Niimura, M. et al. Aph- 1 contributes to the stabilization and trafficking of the γ-secretase complex through mechanisms involving intermolecular and intramolecular interactions. J. Biol. Chem. 280(13), 12967-12975(2005)]. APH-1AL deletion or mutation can lead to the inability to assemble and activate γ-secretase [Lee, S.F. et al. A conserved GXXXG motif in APH-1 iscritical for assembly and activity of the γ-secretase complex. (6), 4144-4152 (2004)]. In order to test whether β-Arrestin1 affects the assembly and activation process of γ-secretase, the inventors used glycerol gradient centrifugation to separate the γ-secretase complex from mouse hippocampus tissue extracts, and analyzed the molecular...

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Abstract

The invention relates to the application of a substance reducing the combination of β-arrestin 1 and APH-1 protein in the preparation of drugs for preventing and treating neurodegenerative diseases. The present invention reveals for the first time that β-Arrestin1 can interact with APH-1, an essential component of γ-secretase, thereby affecting the activity of γ-secretase. The present invention also discloses an isolated protein fragment of APH‑1AL and APH‑1B, the protein fragment is not only the target of the interaction between β-arrestin 1 and γ-secretase-related components, but also can be used to interfere with β ‑Arrestin 1 interacts with APH‑1, thereby inhibiting amyloid production and associated neurodegenerative diseases. The invention also discloses a method for screening drugs for preventing and treating neurodegenerative diseases.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and more specifically relates to a new neurodegenerative disease-related target, an inhibitor based on the target, and a drug screening model and method based on the target. Background technique [0002] Alzheimer's disease is a degenerative disease of the central nervous system mainly characterized by progressive cognitive impairment and memory impairment. The clinical manifestations of patients are cognitive (calculation, judgment, synthesis, etc.) dysfunction, memory loss, and personality abnormalities. The main pathological features of Alzheimer's disease are the formation of amyloid plaques and neurofibrillary tangles in the patient's brain. Amyloid plaques are the characteristic pathological changes of Alzheimer's disease, which are mainly formed by the extracellular accumulation of abnormally large amounts of amyloid-β (Aβ) protein produced in cells. [0003] The cause of Alzheimer's di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61K38/10A61K38/16A61K39/395A61K48/00A61P25/28A61P25/16C07K14/47C07K7/08C12N15/12
Inventor 裴钢赵简刘小松赵晓晖
Owner CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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