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
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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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