Limits...
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.

Show MeSH

Related in: MedlinePlus

RU-505 restored cognitive function in Tg6799 mice. (A) Freezing behavior was measured before electric foot shock during the training day to assess the basal freezing tendency of each group of mice. (n = 8–10 mice per group). (B) Contextual memory was assessed by measuring freezing behavior upon reexposure to the training chamber 24 h after fear conditioning training. (*, P < 0.05; **, P < 0.01; n = 8–10 mice per group). Results are from two independent experiments. (C–E) Spatial learning and memory retention of WT and Tg6799 mice was assessed using the Barnes maze after 3 mo of treatment with RU-505 or vehicle. One target hole was connected to a hidden escape chamber. (C) During training trials, latency to poke the target hole was measured. Significance was assessed using two-way ANOVA analysis with repeated measure (WT/vehicle vs. Tg6799/vehicle: F[1,120] = 40.47; P < 0.001; Tg6799/vehicle vs. Tg6799/RU-505: F[1,108] = 11.97; P < 0.01; n = 10–14 mice per group). Differences in latency were assessed by Bonferroni post hoc analysis. (D–F) During the Barnes maze probe trial, latency to reach the closed target hole (D), number of visits to the target hole (E), and total traveled distance (F) were measured ([E] *, P < 0.05; **, P < 0.01; ***, P < 0.001; n = 10–14 mice per group; [F] ***, P < 0.001; n = 10–14 mice per group). All results of the Barnes maze are from three independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig5: RU-505 restored cognitive function in Tg6799 mice. (A) Freezing behavior was measured before electric foot shock during the training day to assess the basal freezing tendency of each group of mice. (n = 8–10 mice per group). (B) Contextual memory was assessed by measuring freezing behavior upon reexposure to the training chamber 24 h after fear conditioning training. (*, P < 0.05; **, P < 0.01; n = 8–10 mice per group). Results are from two independent experiments. (C–E) Spatial learning and memory retention of WT and Tg6799 mice was assessed using the Barnes maze after 3 mo of treatment with RU-505 or vehicle. One target hole was connected to a hidden escape chamber. (C) During training trials, latency to poke the target hole was measured. Significance was assessed using two-way ANOVA analysis with repeated measure (WT/vehicle vs. Tg6799/vehicle: F[1,120] = 40.47; P < 0.001; Tg6799/vehicle vs. Tg6799/RU-505: F[1,108] = 11.97; P < 0.01; n = 10–14 mice per group). Differences in latency were assessed by Bonferroni post hoc analysis. (D–F) During the Barnes maze probe trial, latency to reach the closed target hole (D), number of visits to the target hole (E), and total traveled distance (F) were measured ([E] *, P < 0.05; **, P < 0.01; ***, P < 0.001; n = 10–14 mice per group; [F] ***, P < 0.001; n = 10–14 mice per group). All results of the Barnes maze are from three independent experiments.

Mentions: Because RU-505 restored Aβ-induced altered thrombosis and impaired fibrinolysis in vitro and in vivo, we explored whether long-term RU-505 treatment could have behavioral effects on AD mice. 7-mo-old Tg6799 mice treated for 3 mo with RU-505 were tested using contextual fear conditioning to assess possible cognitive changes. RU-505 treatment had no effect on baseline freezing behavior in WT and Tg6799 mice (Fig. 5 A). When we evaluated contextual memory of Tg6799 and WT mice 24 h after training, vehicle-treated Tg6799 mice showed a severe memory deficit compared with vehicle-treated WT mice (Fig. 5 B). RU-505–treated Tg6799 mice exhibited significantly improved memory compared with their vehicle-treated AD counterparts, whereas long-term treatment of RU-505 in WT mice did not impact basal freezing behavior or contextual memory.


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)

RU-505 restored cognitive function in Tg6799 mice. (A) Freezing behavior was measured before electric foot shock during the training day to assess the basal freezing tendency of each group of mice. (n = 8–10 mice per group). (B) Contextual memory was assessed by measuring freezing behavior upon reexposure to the training chamber 24 h after fear conditioning training. (*, P < 0.05; **, P < 0.01; n = 8–10 mice per group). Results are from two independent experiments. (C–E) Spatial learning and memory retention of WT and Tg6799 mice was assessed using the Barnes maze after 3 mo of treatment with RU-505 or vehicle. One target hole was connected to a hidden escape chamber. (C) During training trials, latency to poke the target hole was measured. Significance was assessed using two-way ANOVA analysis with repeated measure (WT/vehicle vs. Tg6799/vehicle: F[1,120] = 40.47; P < 0.001; Tg6799/vehicle vs. Tg6799/RU-505: F[1,108] = 11.97; P < 0.01; n = 10–14 mice per group). Differences in latency were assessed by Bonferroni post hoc analysis. (D–F) During the Barnes maze probe trial, latency to reach the closed target hole (D), number of visits to the target hole (E), and total traveled distance (F) were measured ([E] *, P < 0.05; **, P < 0.01; ***, P < 0.001; n = 10–14 mice per group; [F] ***, P < 0.001; n = 10–14 mice per group). All results of the Barnes maze are from three independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig5: RU-505 restored cognitive function in Tg6799 mice. (A) Freezing behavior was measured before electric foot shock during the training day to assess the basal freezing tendency of each group of mice. (n = 8–10 mice per group). (B) Contextual memory was assessed by measuring freezing behavior upon reexposure to the training chamber 24 h after fear conditioning training. (*, P < 0.05; **, P < 0.01; n = 8–10 mice per group). Results are from two independent experiments. (C–E) Spatial learning and memory retention of WT and Tg6799 mice was assessed using the Barnes maze after 3 mo of treatment with RU-505 or vehicle. One target hole was connected to a hidden escape chamber. (C) During training trials, latency to poke the target hole was measured. Significance was assessed using two-way ANOVA analysis with repeated measure (WT/vehicle vs. Tg6799/vehicle: F[1,120] = 40.47; P < 0.001; Tg6799/vehicle vs. Tg6799/RU-505: F[1,108] = 11.97; P < 0.01; n = 10–14 mice per group). Differences in latency were assessed by Bonferroni post hoc analysis. (D–F) During the Barnes maze probe trial, latency to reach the closed target hole (D), number of visits to the target hole (E), and total traveled distance (F) were measured ([E] *, P < 0.05; **, P < 0.01; ***, P < 0.001; n = 10–14 mice per group; [F] ***, P < 0.001; n = 10–14 mice per group). All results of the Barnes maze are from three independent experiments.
Mentions: Because RU-505 restored Aβ-induced altered thrombosis and impaired fibrinolysis in vitro and in vivo, we explored whether long-term RU-505 treatment could have behavioral effects on AD mice. 7-mo-old Tg6799 mice treated for 3 mo with RU-505 were tested using contextual fear conditioning to assess possible cognitive changes. RU-505 treatment had no effect on baseline freezing behavior in WT and Tg6799 mice (Fig. 5 A). When we evaluated contextual memory of Tg6799 and WT mice 24 h after training, vehicle-treated Tg6799 mice showed a severe memory deficit compared with vehicle-treated WT mice (Fig. 5 B). RU-505–treated Tg6799 mice exhibited significantly improved memory compared with their vehicle-treated AD counterparts, whereas long-term treatment of RU-505 in WT mice did not impact basal freezing behavior or contextual memory.

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