Small molecule compound and application thereof in preparation of related products for treating or preventing Alzheimer's disease

A small molecular compound, Alzheimer's disease technology, applied in the field of biomedicine, can solve the problems of degrading protease dysfunction, aggravating cognitive function, degeneration, etc., and achieve the goal of reducing the production of Aβ protein, broadening the selection field, and inhibiting expression Effect

Inactive Publication Date: 2022-01-18
蒋青 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, current studies believe that in the preclinical stage of Alzheimer's disease, the clearance efficiency of AβO in the cerebrospinal fluid may decrease and the concentration of AβO in the cerebrospinal fluid may increase, which may be related to the dysfunction of these degradation proteases
In addition, not all AβO can be cleared, and some oligomers dissociated from Aβ fibrils may not be cleared and have some toxicity to adjacent synapses, promoting the hyperphosphorylation and aggregation of microtubule-associated Tau protein , so that it loses the role of binding and stabilizing microtubules, aggregates to form pairs of helical filaments, and aggravates the degeneration of cognitive function

Method used

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  • Small molecule compound and application thereof in preparation of related products for treating or preventing Alzheimer's disease
  • Small molecule compound and application thereof in preparation of related products for treating or preventing Alzheimer's disease
  • Small molecule compound and application thereof in preparation of related products for treating or preventing Alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Embodiment 1 Experimental material

[0021] 1.1 Preparation of GSK 3 Inhibitor IX (6-Bromoindirubin-3'-oxime; BIO) GSK 3 Inhibitor IX (6-Bromoindirubin-3'-oxime; BIO) with a purity of 99.66% was purchased from MCE Company (MedChemExpress.Co), Its chemical structural formula is as follows:

[0022]

[0023] Dissolve the purchased GSK 3 Inhibitor IX (6-Bromoindirubin-3'-oxime; BIO) powder in DMSO to prepare GSK 3 Inhibitor IX (BIO) with a concentration of 10mM, aliquot and store frozen for later use, dilute with DMSO when used into the corresponding concentration.

[0024] 1.2 Alzheimer's cell model (N2a-APP cells) preparation

[0025] The construction method of N2a-APP cell line is as follows:

[0026] 1. Experimental materials:

[0027] 1. Cell line and lentivirus:

[0028] Virus (pRLenti-CMV-MCS-3FLAG-PGK-Puro, and metaconstruct: GL102);

[0029] Virus (pRLenti-CMV-APP695swe(K595N / M596L)-3FLAG-PGK-Puro, and element construction: H13319); Neuro-2a cells are fro...

Embodiment 2

[0051] Example 2 GSK 3 Inhibitor IX (6-Bromoindirubin-3'-oxime; BIO) inhibits BACE1 expression on Wnt signal activation

[0052] In order to verify the effect of GSK 3 Inhibitor IX (6-Bromoindirubin-3'-oxime; BIO) on the nervous system, different concentrations of BIO (2uM, 5uM) were added to the nerve cell line N2a cells prepared in Example 1, and the cells were detected after 24 hours The protein content of Wnt signaling pathway, to clarify the activation effect of BIO on Wnt signaling of nerve cells. Specifically, in order to detect the expression of BIO on BACE1 protein, the expression level of BACE1 mRNA in N2a cells was detected after 24 hours, and it was found that BIO could significantly inhibit the expression of BACE1 mRNA ( figure 1 (A)).

[0053] In addition, after adding different concentrations of BIO (2uM, 5uM) to the neural cell line N2a cells and culturing them for 48 hours, it was found that the intracellular β-catenin protein content increased significantly,...

Embodiment 3

[0054] Example 3 GSK 3 Inhibitor IX (6-Bromoindirubin-3'-oxime; BIO) inhibits the production of Aβ protein

[0055] In order to clarify that GSK 3 Inhibitor IX (6-Bromoindirubin-3'-oxime; BIO) is involved in the production of Aβ protein by activating Wnt signaling, we constructed the N2a-APP Alzheimer cell model and added 2uM concentration of BIO to it for 24 hours After collecting the supernatant of the cell culture medium, the concentration of Aβ40 and Aβ42 in the supernatant was detected by ELISA, and the concentration of Aβ40 and Aβ42 in the BIO group was significantly reduced. This indicated that GSK 3Inhibitor IX (6-Bromoindirubin-3'-oxime; BIO) could significantly inhibit the production of Aβ protein.

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Abstract

The invention belongs to novel application in the field of biological medicine, belongs to the field of research of related medicines for Alzheimer's disease, and particularly relates to a small molecule compound and application thereof in preparation of related products for treating or preventing Alzheimer's disease. According to the invention, research results show that a GSK 3 inhibitor IX (6-Bromoindirubin-3'-oxime, BIO) can inhibitGsk3beta so as to inhibit the expression of BACE1 in cells and reduce the production process of A beta protein, so the GSK 3 inhibitor IX can be further utilized to prepare the related products for treating and / or preventing Alzheimer's disease. Thus, a brand-new choice and thought are provided for the medicines for treating the Alzheimer's disease at present, and the selection field of the medicines for treating the Alzheimer's disease is widened.

Description

technical field [0001] The invention relates to a new application in the field of biomedicine, belongs to the field of drug research related to Alzheimer's disease, and specifically relates to a small molecule compound and its application in preparing related products for treating or preventing Alzheimer's disease. Background technique [0002] Alzheimer's disease (AD) is a gradually aggravating neurodegenerative disease that widely affects the cerebral cortex and hippocampus of patients, leading to progressive memory loss and seriously affecting the cognitive function of normal elderly people. It brings serious living burden to patients, and also brings heavy economic pressure to society. By 2018, about 44 million people worldwide will suffer from Alzheimer's disease, and this number will reach 150 million in 2050. However, the specific mechanism is not very clear, and there is no significantly improved drug treatment. [0003] At present, the pathogenesis of Alzheimer's d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/40A61P25/28A61K31/404
CPCC07D209/40A61P25/28A61K31/404
Inventor 蒋青石天舒郭保生陈响施勇沈思虞马宇泽
Owner 蒋青
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