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A novel Aβ-fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer's disease mice.

Ahn HJ, Glickman JF, Poon KL, Zamolodchikov D, Jno-Charles OC, Norris EH, Strickland S - J. Exp. Med. (2014)

Bottom Line: To determine if the Aβ-fibrinogen interaction could be targeted as a potential new treatment for AD, we designed a high-throughput screen and identified RU-505 as an effective inhibitor of the Aβ-fibrinogen interaction.Furthermore, long-term treatment of RU-505 significantly reduced vascular amyloid deposition and microgliosis in the cortex and improved cognitive impairment in mouse models of AD.Our studies suggest that inhibitors targeting the Aβ-fibrinogen interaction show promise as therapy for treating AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Neurobiology and Genetics and High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065.

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Long-term treatment with RU-505 reduced the level of infiltrated fibrinogen and microgliosis in the cortex of Tg6799 mice. (A) Fibrinogen localized outside of endothelial cells of blood vessels was labeled with FITC-conjugated antifibrinogen antibody (green), and endothelial cells were labeled using anti-CD31 antibody (red; bars, 50 µm). (B) Activated microglia were visualized by staining for CD11b (red). DAPI staining (blue) was used to show integrity of tissue (bars, 100 µm). (C and D) Total fibrinogen area (C) and microgliosis (D) were quantified from 3 sections per mouse (n = 3–4 mice per group; *, P < 0.05; ***, P < 0.001). All values are means and SEM. Results are from two independent experiments.
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fig7: Long-term treatment with RU-505 reduced the level of infiltrated fibrinogen and microgliosis in the cortex of Tg6799 mice. (A) Fibrinogen localized outside of endothelial cells of blood vessels was labeled with FITC-conjugated antifibrinogen antibody (green), and endothelial cells were labeled using anti-CD31 antibody (red; bars, 50 µm). (B) Activated microglia were visualized by staining for CD11b (red). DAPI staining (blue) was used to show integrity of tissue (bars, 100 µm). (C and D) Total fibrinogen area (C) and microgliosis (D) were quantified from 3 sections per mouse (n = 3–4 mice per group; *, P < 0.05; ***, P < 0.001). All values are means and SEM. Results are from two independent experiments.

Mentions: Therefore, we measured the level of infiltrated fibrinogen and microgliosis in the cortex of Tg6799 or WT littermate mice after RU-505 treatment. We quantified fibrinogen deposition (green; Fig. 7 A) outside the endothelial cells of blood vessels that were labeled using CD31 (red; Fig. 7 A), and the area of activated microglia that were labeled using CD11b (red; Fig. 7 B). The levels of infiltrated fibrinogen and microgliosis were highly increased in the cortex of Tg6799 compared with WT mice (Fig. 7, C and D), and these increases were significantly decreased by RU-505 (Fig. 7, C and D).


A novel Aβ-fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer's disease mice.

Ahn HJ, Glickman JF, Poon KL, Zamolodchikov D, Jno-Charles OC, Norris EH, Strickland S - J. Exp. Med. (2014)

Long-term treatment with RU-505 reduced the level of infiltrated fibrinogen and microgliosis in the cortex of Tg6799 mice. (A) Fibrinogen localized outside of endothelial cells of blood vessels was labeled with FITC-conjugated antifibrinogen antibody (green), and endothelial cells were labeled using anti-CD31 antibody (red; bars, 50 µm). (B) Activated microglia were visualized by staining for CD11b (red). DAPI staining (blue) was used to show integrity of tissue (bars, 100 µm). (C and D) Total fibrinogen area (C) and microgliosis (D) were quantified from 3 sections per mouse (n = 3–4 mice per group; *, P < 0.05; ***, P < 0.001). All values are means and SEM. Results are from two independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4042638&req=5

fig7: Long-term treatment with RU-505 reduced the level of infiltrated fibrinogen and microgliosis in the cortex of Tg6799 mice. (A) Fibrinogen localized outside of endothelial cells of blood vessels was labeled with FITC-conjugated antifibrinogen antibody (green), and endothelial cells were labeled using anti-CD31 antibody (red; bars, 50 µm). (B) Activated microglia were visualized by staining for CD11b (red). DAPI staining (blue) was used to show integrity of tissue (bars, 100 µm). (C and D) Total fibrinogen area (C) and microgliosis (D) were quantified from 3 sections per mouse (n = 3–4 mice per group; *, P < 0.05; ***, P < 0.001). All values are means and SEM. Results are from two independent experiments.
Mentions: Therefore, we measured the level of infiltrated fibrinogen and microgliosis in the cortex of Tg6799 or WT littermate mice after RU-505 treatment. We quantified fibrinogen deposition (green; Fig. 7 A) outside the endothelial cells of blood vessels that were labeled using CD31 (red; Fig. 7 A), and the area of activated microglia that were labeled using CD11b (red; Fig. 7 B). The levels of infiltrated fibrinogen and microgliosis were highly increased in the cortex of Tg6799 compared with WT mice (Fig. 7, C and D), and these increases were significantly decreased by RU-505 (Fig. 7, C and D).

Bottom Line: To determine if the Aβ-fibrinogen interaction could be targeted as a potential new treatment for AD, we designed a high-throughput screen and identified RU-505 as an effective inhibitor of the Aβ-fibrinogen interaction.Furthermore, long-term treatment of RU-505 significantly reduced vascular amyloid deposition and microgliosis in the cortex and improved cognitive impairment in mouse models of AD.Our studies suggest that inhibitors targeting the Aβ-fibrinogen interaction show promise as therapy for treating AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Neurobiology and Genetics and High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065.

Show MeSH
Related in: MedlinePlus