Application of TLR3 receptor agonist in preparation of Alzheimer disease neuroprotective agent medicine

Abstract

The invention discloses an application of a TLR3 receptor agonist Poly (I: C) in preparation of a neuroprotective agent drug for Alzheimer's disease. Belongs to the technical field of Alzheimer disease medicines. The TLR3 agonist Poly (I: C) is used for preparing the Alzheimer disease neuroprotective agent medicine to play a brain protection role in Alzheimer disease, specifically, the TLR3 agonist Poly (I: C) is used for removing deposition of Abeta1-42 in the brain, reducing Abeta1-42 in plasma and improving encephalatrophy, and meanwhile, the learning and memory ability of mice with the Alzheimer disease can be remarkably reduced.

Description

Technical Field:

[0001] The present invention relates to the technical field of Alzheimer's disease drugs, and particularly relates to the application of TLR3 receptor agonists as drugs for preparing Alzheimer's disease neuroprotective agents. Background Art:

[0002] Alzheimer's disease (AD) is a chronic, neurodegenerative disease and the most common type of dementia. The Alzheimer's Disease International (ADI) estimated in 2019 that the number of people suffering from dementia globally would reach 50 million, and it is expected to reach 150 million in 2050. Currently, the global annual cost for treating dementia patients reaches $1 trillion, and it is expected to double by 2030. AD patients bring a heavy medical burden and social burden to families and society.

[0003] The pathogenesis of Alzheimer's disease has not been fully elucidated. Currently, the deposition of β-amyloid protein (Aβ) is the generally recognized core pathological hypothesis for AD. In recent years, more and more studies have shown that persistent immune inflammation in the brain has become another core pathological change in AD. Under the continuous stimulation of Aβ in the brain, a large number of glial cells are activated, disrupting the stable environment of pro-inflammatory and anti-inflammatory factors in the brain and breaking the balance, thus leading to the persistence of chronic neuroinflammation, which is closely related to the release of a large number of inflammatory factors by the activated glial cells. When the initial Aβ plaques activate glial cells, they can phagocytize Aβ and reduce the toxicity of Aβ. However, when the Aβ plaques persist, it leads to the over-activation of glial cells, releasing a large number of harmful inflammatory substances and causing a chronic inflammatory response, resulting in neuronal dysfunction and neuronal loss. The persistent neuroinflammatory response not only leads to neuronal loss and neurodegeneration, but also plays a connecting role between the Aβ mechanism and the Tau-NFT mechanism, exacerbating the pathological changes of Aβ, tau protein, and NFT and promoting the progression of AD.

[0004] Toll-like receptors (TLRs) are a superfamily of type I transmembrane receptors and are pattern recognition receptors in the innate immune system. They play an important role in the induction and regulation of immune inflammatory responses. TLRs are activated by binding to ligands and, through their regulatory proteins, activate protein kinases on their downstream pathways, leading to the activation of nuclear transcription factor (NF-κB) and interferon regulatory factor (IRF), thereby inducing and regulating the release of immune inflammatory factors. Research shows that the TLR3 agonist Poly(I:C) is beneficial for the repair of nervous system diseases such as bacterial encephalitis and cerebral ischemia. Considering the regulatory effect of TLR3 on neuroinflammation and the role of neuroinflammation in AD, TLR3 agonists are expected to slow down the pathological progression of AD and improve cognitive function.

[0005] The information disclosed in this background section is only intended to enhance the overall understanding of the background of the present invention and should not be regarded as an admission or any form of implication that this information constitutes prior art already known to those of ordinary skill in the art. Summary of the Invention:

[0006] The object of the present invention is to provide the application of the TLR3 receptor agonist Poly(I:C) as a drug for neuroprotection in Alzheimer's disease, so as to slow down the pathological progression of Alzheimer's disease and improve cognitive function, and to provide neuroprotection.

[0007] The present invention provides the application of the TLR3 receptor agonist Poly(I:C) as a drug for preparing a neuroprotective agent for Alzheimer's disease.

[0008] Furthermore, preferably, the TLR3 receptor agonist Poly(I:C) is dissolved in physiological saline, and every 1 mg of Poly(I:C) is dissolved in 1 ml of physiological saline.

[0009] Furthermore, preferably, the dosage of the TLR3 receptor agonist Poly(I:C) as a drug for preparing a neuroprotective agent for Alzheimer's disease is 5 mg / kg.

[0010] Furthermore, preferably, the using method of the TLR3 receptor agonist Poly(I:C) as a drug for preparing a neuroprotective agent for Alzheimer's disease is intraperitoneal injection.

[0011] Compared with the prior art, the present invention has the following beneficial effects:

[0012] The TLR3 agonist Poly(I:C) of the present invention plays a role in brain protection as a drug for preparing a neuroprotective agent for Alzheimer's disease, specifically manifested as clearing Aβ deposition in the brain, reducing Aβ1-42 in plasma, improving the situation of brain atrophy, and at the same time significantly reducing the learning and memory ability of Alzheimer's disease mice. Brief Description of the Drawings:

[0013] Figure 1 It is a schematic diagram of magnetic resonance T2-weighted image scanning of each group after 3 months of treatment with the TLR3 receptor agonist Poly(I:C) as a protective drug;

[0014] Figure 2 It is a schematic diagram of the deposition of Aβ1-42 in the brain of each group after 3 months of treatment with the TLR3 receptor agonist Poly(I:C) as a protective drug;

[0015] Figure 3 It is a schematic diagram of the content of Aβ1-42 in plasma of each group after 3 months of treatment with the TLR3 receptor agonist Poly(I:C) as a protective drug;

[0016] Figure 4 Schematic diagram of the effect of the TLR3 receptor agonist Poly(I:C) as a protective drug on the learning ability levels of each group after 3 months of treatment;

[0017] Figure 5 Schematic diagram of the effect of the TLR3 receptor agonist Poly(I:C) as a protective drug on the memory ability levels of each group after 3 months of treatment. Specific implementation method:

[0018] The following is a detailed description of the specific implementation method of the present invention, but it should be understood that the protection scope of the present invention is not limited by the specific implementation method.

[0019] Breed and establish APP / PSEN1 (AD) and littermate control (WT) mouse strains.

[0020] Divide the mice into 4 groups, namely: AD+Saline group (saline group), AD+Poly(I:C) group (TLR3 receptor agonist group), WT+Saline group (saline group), WT+Poly(I:C) group (TLR3 receptor agonist group). Administer Poly(I:C) or saline treatment (intraperitoneal injection, once every 4 days for 3 consecutive months) to each group of 12-month-old mice and record the changes in the body weight of the mice.

[0021] Example 1: Evaluation of cerebral atrophy in mice.

[0022] Perform T2WI scans of MRI on 4 groups of mice to detect the thickness of the cerebral cortex and the volume of the hippocampus. The statistical results of the T2WI images show that the thickness of the cerebral cortex of the mice in the AD+Saline group is significantly thinner than that in the WT+Saline group, the thickness of the cerebral cortex of the mice in the AD+Poly(I:C) group is significantly increased compared with that in the AD+Saline group, the volume of the hippocampus of the mice in the AD+Saline group is significantly smaller than that in the WT+Saline group, and the volume of the hippocampus of the mice in the AD+Poly(I:C) group is significantly increased compared with that in the AD+Saline group. The scanning results are as Figure 1 shown, where A is the MRI image, B is the statistical result of the thickness of the cerebral cortex of the mice, and C is the statistical result of the volume of the hippocampus of the mice.

[0023] Example 2: Effect on Aβ deposition in the brain of mice.

[0024] Detect the expression of the main toxic subtype Aβ1-42 in the brain by immunofluorescence staining and Western Blot.

[0025] The results of Aβ1-42 immunofluorescence staining showed that there was no obvious positive staining of Aβ1-42 in the brains of mice in the WT group. The deposition of Aβ1-42 in the hippocampus and cortex of mice in the AD+Poly(I:C) group was significantly reduced compared with that in the AD+Saline group, and the results were as shown in Figure 2 A and B below;

[0026] The Western Blot method was used to further verify the results of immunofluorescence. The results showed that compared with the mice in the WT+Saline group, the expression of Aβ1-42 protein in the cerebral cortex and hippocampus of mice in the AD+Saline group was significantly increased, while the expression of Aβ1-42 protein in the cerebral cortex and hippocampus of mice in the AD+Poly(I:C) group was significantly less than that in the AD+Saline group, and the results were as shown in Figure 2 C and D below.

[0027] Example 3: Evaluate the content of Aβ in the plasma of mice.

[0028] The content of Aβ protein in the peripheral plasma of mice was detected. The results showed that the content of Aβ1-42 in the plasma of mice in the AD+Saline group was significantly higher than that in the WT+Saline group, and the content of Aβ1-42 in the AD+Poly(I:C) group was significantly lower than that in the AD+Saline group, as shown in Figure 3 A below; the content of Aβ1-40 in the plasma of mice in the AD+Saline group was significantly higher than that in the WT+Saline group, and the content of Aβ1-40 in the AD+Poly(I:C) group was significantly lower than that in the AD+Saline group, as shown in Figure 3 B below.

[0029] These results suggest that intraperitoneal injection of Poly(I:C) significantly reduces the content of Aβ1-40 and Aβ1-42 in the serum of AD mice.

[0030] Example 4: Evaluate the learning ability of mice.

[0031] In the positioning cruise experiment stage of the water maze, the results showed that compared with the mice in the WT+Saline group, the time required for the mice in the AD+Saline group to find the platform was significantly prolonged. In contrast, the time required for the mice in the AD+Poly(I:C) group to find the platform was significantly shorter than that in the AD+Saline group, as shown in Figure 4 A and B below.

[0032] Example 5: Evaluate the memory level of mice.

[0033] During the spatial exploration phase of the water maze, the results showed that the activity time of the AD+Saline group mice in the target quadrant was significantly shorter than that of the WT+Saline group, while the activity time of the AD+Poly(I:C) group mice in the target quadrant was significantly longer than that of the AD+Saline group, as Figure 5 shown in C;

[0034] There was no significant difference in the swimming speed of the mice in each group, suggesting that the results of the mouse water maze were not interfered by the swimming speed, as Figure 5 shown in F;

[0035] The distance that the AD+Saline group mice moved in the target quadrant was significantly shorter than that of the WT+Saline group, while the distance that the AD+Poly(I:C) group mice moved in the target quadrant was significantly longer than that of the AD+Saline group, as Figure 5 shown in E;

[0036] Compared with the WT+Saline group mice, the number of times the AD+Saline group mice crossed the platform was significantly reduced. The number of times the AD+Poly(I:C) group mice crossed the platform was slightly higher than that of the AD+Saline group, but there was no statistical difference, as Figure 5 shown in D.

[0037] In summary, the TLR3 receptor agonist Poly(I:C) has a brain-protective effect on Alzheimer's disease.

[0038] Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. Any person familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be defined by the claims.

Claims

1. Application of TLR3 receptor agonists as neuroprotective drugs for Alzheimer's disease.

2. The use according to claim 1, characterized in that: The TLR3 receptor agonist is dissolved in physiological saline, and each 1 mg of TLR3 receptor agonist is dissolved in 1 ml of physiological saline.

3. The use according to claim 1, characterized in that: The dosage of the TLR3 receptor agonist used as a neuroprotective agent for preparing Alzheimer's disease is 5 mg / kg.

4. The use according to claim 1, characterized in that: The TLR3 receptor agonist is used as a drug for preparing a neuroprotective agent for Alzheimer's disease by intraperitoneal injection.

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