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Application of macrophage migration body as cerebral amyloid vascular disease treatment target

A technology for macrophages and vascular diseases, applied in the field of biomedicine, can solve the problems of accelerated amyloid deposition and clinical effect disputes, and achieve the effect of strong targeting and small side effects

Pending Publication Date: 2022-08-05
THE THIRD AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are also reports that these drugs can accelerate the deposition of amyloid at the same time, so their clinical effects are still controversial.

Method used

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  • Application of macrophage migration body as cerebral amyloid vascular disease treatment target
  • Application of macrophage migration body as cerebral amyloid vascular disease treatment target
  • Application of macrophage migration body as cerebral amyloid vascular disease treatment target

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1. Macrophage-derived migratory bodies are associated with the pathophysiology of cerebral amyloid angiopathy (CAA)

[0031] To detect pathological changes in blood vessels in CAA patients, CAA patient skin biopsies were performed, and the samples were examined by transmission electron microscopy (TEM). We detected multiple deposits of migratory bodies in skin vessels of CAA patients ( figure 1 A). The migratory bodies deposited in skin blood vessels are large oval vesicles with a diameter of 0.5–3.0 μm containing small vesicles, which is consistent with the reported structure of migratory bodies (Ma L, Li Y, Peng J, Wu D, Zhao X, Cui Y, et al. Discovery of themigrasome, an organelle mediating release of cytoplasmic contents during cellmigration. Cell Res. 2015;25(1):24-38.). We observed that migratory bodies are not only located in the vascular lumen ( figure 1 a and b in A), but also within the vessel wall ( figure 1 c and d) in A (emphasized with yellow a...

Embodiment 2

[0032] Example 2. Amyloid beta 1-40 (Aβ40) is an essential inducer of extra migratory body production in macrophages

[0033] Considering that Aβ40 plays a crucial role in CAA progression and that macrophages are the main scavengers of blood vessels, we evaluated the effect of Aβ40 phagocytosis on migrating bodies in cells of the monocyte / microglia / macrophage lineage. produced impact. Human monocytes were isolated from the peripheral blood of healthy donors (healthy controls, HC) and processed with CAA patient plasma. By immunostaining, we found that CAA plasma induces contraction of fibers in monocytes that associate with TSPAN4-expressing oval vesicles, consistent with the described migratory body architecture (Ma L, Li Y, Peng J, Wu D , Zhao X, Cui Y, et al. Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration. Cell Res. 2015;25(1):24-38.)( figure 2 A). At the same time, TSPAN4 expression in monocytes was increased upo...

Embodiment 3

[0034] Example 3. Macrophage-derived migratory bodies have a disruptive effect on the blood-brain barrier (BBB)

[0035] The pathogenicity of migratory bodies derived from Aβ40-stimulated macrophages was further explored. Transfer of migratory bodies (10 mg / kg, iv, injected on days 1, 2, 3, and 5) from Aβ40-stimulated Raw264.7 cells (mouse mononuclear macrophage leukemia cells) into wild-type healthy C57 / BL6 mice (age = 8-10w). On day 7, each mouse was injected with a single dose of 555-dextran (555-Dex, 3 kDa, red, 10 mg / kg, i.v.) 90 minutes before sacrifice ( image 3 A). After the peripheral blood was collected, the mouse heart was perfused with PBS. We found that administration of Aβ40 to stimulate macrophage-generated migratory bodies resulted in downregulation of Claudin in recipient mice ( image 3 B), BBB damage was also significantly increased, showing that 555-Dex leaked significantly in the brain parenchyma of recipient mice of migratory bodies produced by Aβ40...

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Abstract

The invention discloses an application of a macrophage migration body as a cerebral amyloid vascular disease treatment target. According to the application disclosed by the invention, it is found for the first time that migratory bodies generated by A beta40-induced macrophages are related to pathophysiological processes of CAA, the migratory bodies derived from the macrophages damage blood-brain barriers in the CAA through complement-dependent cytotoxic effects, and macrophage apoptosis inhibition factors CD5L stop on blood vessel walls through the migratory bodies derived from the macrophages; the macrophage cell apoptosis inhibition factor CD5L can be used for promoting complement-dependent cytotoxic effect in CAA, so that the macrophage-derived migration body and the macrophage apoptosis inhibition factor CD5L can be used as new targets for CAA treatment. A reagent for inhibiting formation of macrophage migration bodies and expression of macrophage apoptosis inhibiting factors CD5L is developed to prepare a medicine for preventing and treating CAA, and compared with an immunosuppressor and glucocorticoid which are wide in action range, the reagent has the advantage of being high in targeting performance and small in side effects such as bleeding transformation, hepatorenal toxicity and A beta deposition.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to the application of macrophage migration body as a therapeutic target for cerebral amyloid angiopathy. Background technique [0002] Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease characterized by dementia, psychiatric symptoms, and recurrent or multiple lobar hemorrhage. . In addition to the obvious high incidence, the disease also has age-related characteristics in elderly patients, among which: CAA patients account for 4.7% to 9% of the patients aged 60 to 69 years old, but those over 90 years old. In the population, this number rose to 43% to 58%. The pathophysiological mechanism of CAA is due to the deposition of β-amyloid (amyloidβ-protein, Aβ) on the walls of large arteries, arterioles and capillaries, mainly in the cerebrovascular system, especially the pia mater and cortical vessels. Accumulated Aβ can lead to the loss of smooth muscle c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/02G01N33/68A61K39/395A61K45/00A61P25/28
CPCG01N33/6893G01N33/5005A61K45/00A61K39/395A61P25/28G01N2800/2871
Inventor 陆正齐胡梦颜蔡蔚李春仪苏晓桃陆丹骊李铁梅黄惠蓬邓晓晖
Owner THE THIRD AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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