CN-121987798-A - Application of IL-17A inhibitor in preparation of medicine for treating Alzheimer disease

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to an application of an IL-17A inhibitor in preparation of a medicine for treating Alzheimer disease, wherein the IL-17A inhibitor is an anti-IL-17A neutralizing antibody and/or an intestinal flora scavenger. The invention inhibits IL-17A signal through IL-17A inhibitor, blocks or lightens the pericyte coke death related to NLRP3 inflammatory corpuscles, thereby realizing the maintenance or recovery of pericyte coverage and steady state, improving brain micro-vascular structure, reducing blood-brain barrier leakage, improving cognitive function, and being applicable to the prevention and treatment research and drug development of Alzheimer disease and related cognitive dysfunction.

Inventors

• LUO QINGHUA
• LI FANG
• ZHU XINGEN
• Tu Jianglong
• Yan Tengfeng
• YANG LI
• ZHU WENPING
• ZHU ZIJING

Assignees

• 南昌大学第二附属医院

Dates

Publication Date

20260508

Application Date

20260409

Claims (5)

1. 1. The use of an IL-17A inhibitor for the manufacture of a medicament for the amelioration of brain microvascular dysfunction associated with alzheimer's disease, characterized in that said IL-17A inhibitor is an anti-IL-17A neutralizing antibody and/or an intestinal flora scavenger.
2. 2. The application of the IL-17A inhibitor in preparing medicaments for reducing brain microvascular pericyte coke apoptosis related indexes is characterized in that the IL-17A inhibitor is an anti-IL-17A neutralizing antibody and/or an intestinal flora scavenger.
3. 3. The use according to claim 1 or 2, wherein the IL-17A inhibitor is an siRNA of IL17ra and/or Traf3ip 2.
4. 4. The use according to claim 3, wherein the sense strand of said siRNA to Il17ra is shown in SEQ ID NO. 1, the antisense strand is shown in SEQ ID NO. 2, the sense strand of said siRNA to Traf3ip2 is shown in SEQ ID NO. 3, and the antisense strand is shown in SEQ ID NO. 4.
5. 5. The use according to claim 1 or 2, wherein the intestinal flora scavenger is an antibiotic cocktail.

Description

Application of IL-17A inhibitor in preparation of medicine for treating Alzheimer disease Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to an application of an IL-17A inhibitor in preparation of a medicine for treating Alzheimer disease. Background In addition to classical amyloid and Tau pathology, alzheimer's Disease (AD) has increasingly demonstrated that cerebrovascular dysfunction and blood-brain barrier disruption are important events in the early stages of the disease. The peripheral cells of the brain microvessels are key components of neurovascular units and are involved in maintaining the stability of capillaries and regulating the expression of blood-brain barrier tight junction proteins and vascular permeability. In one aspect, reduced pericyte numbers or impaired function can lead to reduced microvascular density, reduced tight junctions (e.g., ZO-1, occludin) and leakage of the blood-brain barrier, thereby accelerating neuroinflammation and cognitive decline. On the other hand, the interaction of the intestinal flora with the immune system may influence the course of diseases of the central nervous system. Studies have shown that peripheral Th17 cells and their secreted IL-17A may be involved in neuroinflammation and brain injury. However, the prior art still has at least the following disadvantages of (1) lack of definite research on mechanisms related to intestinal flora-Th 17/IL-17A-pericyte injury, especially lack of elucidation on pericyte specific injury modes, (2) lack of operable and convertible target strategies for simultaneously realizing pericyte protection, blood-brain barrier repair and cognition improvement, and (3) lack of intervention on cerebral microvascular dysfunction by using the existing AD to treat multi-focus neurons or amyloid related targets, and limited curative effects. Therefore, a new technical scheme is needed to be provided, which can inhibit the critical path causing the pericyte injury based on a definite target mechanism, so as to realize the protection and improvement of cerebral microvascular and cognitive functions. Disclosure of Invention Aiming at the defects of the prior art, the invention aims to provide an application of an IL-17A inhibitor in preparing a medicament for treating Alzheimer's disease, and the inhibitor can inhibit IL-17A signals, block or lighten pericyte coke death related to NLRP3 inflammatory corpuscles, thereby realizing maintenance or restoration of pericyte coverage and steady state, improving brain microvascular structure, reducing blood-brain barrier leakage and improving cognitive function, and can be used for prevention and treatment research and medicament development of Alzheimer's disease and related cognitive disorders. In order to achieve the above purpose, the technical scheme of the invention is realized as follows: Through exploring molecular mechanisms of intestinal flora-immune inflammation-brain microvascular injury under the condition of Alzheimer disease, the inventor discovers that 1) in an APP/PS1 mouse, the level of peripheral IL-17A is increased and is accompanied with abnormal accumulation of brain Th17 cells, and brain microvascular structure damage, blood-brain barrier leakage increase, pericyte coverage reduction and other brain vascular dysfunction phenotypes appear simultaneously, 2) the peripheral cell injury and inflammatory small body/coke death related molecular change are accompanied by the up-regulation of NLRP3 inflammatory small body and coke death related protein expression in the brain microvascular of the APP/PS1 mouse, 3) the intestinal flora clearance (antibiotic cocktail, ABX) can reduce peripheral IL-17A and the accumulation of brain pathogenic Th17 cells, and simultaneously improve brain microvascular structure and blood-brain barrier related indexes, increase pericyte coverage and reduce pericyte coke death related marks, 4) in vitro experiments show that IL-17A can directly Act on primary brain pericyte, up-regulate IL-17 signal key molecules and induce the up-regulation of NLRP3 inflammatory small body/coke death related protein expression, 3) the clearance of the intestinal flora can reduce the IL-17A and inhibit the activity of the IL-17 at the same time as the IL-17A in the brain microvascular blood vessel of the APP/PS1 mouse and the brain microvascular injury related protein, and the IL-17A can inhibit the activity of the IL-17A and inhibit the activity of the tumor-related protein from being increased in the brain tumor cells and the brain-related protein from the tumor cells and inhibit the activity of the tumor-related protein from the tumor cells. Accordingly, a first object of the present invention is to provide the use of an IL-17A inhibitor for the preparation of a medicament for improving Alzheimer's disease-associated brain microvascular dysfunction. The second object of the invention is to provide an appli