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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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RU-505 restored spatial retention memory in TgCRND8 mice without affecting motor behavior. (A) The spatial memory of vehicle- or RU-505–treated WT and TgCRND8 mice was assessed using Barnes maze. (B and C) Spatial memory of RU-505–treated WT and TgCRND8 mice was tested using the Barnes maze probe trials. Time to reach the target hole (B), the number of visits to the closed target hole (C), and total distance traveled (D) were assessed (n = 7–11 mice per group). The results corroborate those in Fig. 5 and are from one experiment. All values are means and SEM.
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fig6: RU-505 restored spatial retention memory in TgCRND8 mice without affecting motor behavior. (A) The spatial memory of vehicle- or RU-505–treated WT and TgCRND8 mice was assessed using Barnes maze. (B and C) Spatial memory of RU-505–treated WT and TgCRND8 mice was tested using the Barnes maze probe trials. Time to reach the target hole (B), the number of visits to the closed target hole (C), and total distance traveled (D) were assessed (n = 7–11 mice per group). The results corroborate those in Fig. 5 and are from one experiment. All values are means and SEM.

Mentions: To further address any possible issue of hypoactivity in the Tg6799 mice and to test whether RU-505 treatment had a similar effect on a different strain of AD transgenic mice, we administered RU-505 to 4-mo-old TgCRND8 mice (Chishti et al., 2001) for 3 mo (analyzed at 7 mo-of-age) as a pilot experiment. During training, RU-505 treatment did not lead to improvement in spatial learning in TgCRND8 mice (Fig. 6 A); however, this treatment significantly reduced the latency to reach the target hole during the probe trial compared with vehicle-treated TgCRND8 mice (Fig. 6 B). Furthermore, the number of visits to the target hole during the probe trial was significantly higher in RU-505–treated TgCRND8 mice compared with vehicle-treated TgCRND8 mice (Fig. 6 C). In addition, vehicle-treated TgCRND8 mice showed similar locomotor activity during probe trials (Fig. 6 D), indicating that the impaired performance of vehicle-treated TgCRND8 mice in Barnes maze test is more likely caused by deficits in spatial memory. These results suggest that treatment of RU-505 substantially improved the deficits in spatial memory of TgCRND8 mice.


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 spatial retention memory in TgCRND8 mice without affecting motor behavior. (A) The spatial memory of vehicle- or RU-505–treated WT and TgCRND8 mice was assessed using Barnes maze. (B and C) Spatial memory of RU-505–treated WT and TgCRND8 mice was tested using the Barnes maze probe trials. Time to reach the target hole (B), the number of visits to the closed target hole (C), and total distance traveled (D) were assessed (n = 7–11 mice per group). The results corroborate those in Fig. 5 and are from one experiment. All values are means and SEM.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig6: RU-505 restored spatial retention memory in TgCRND8 mice without affecting motor behavior. (A) The spatial memory of vehicle- or RU-505–treated WT and TgCRND8 mice was assessed using Barnes maze. (B and C) Spatial memory of RU-505–treated WT and TgCRND8 mice was tested using the Barnes maze probe trials. Time to reach the target hole (B), the number of visits to the closed target hole (C), and total distance traveled (D) were assessed (n = 7–11 mice per group). The results corroborate those in Fig. 5 and are from one experiment. All values are means and SEM.
Mentions: To further address any possible issue of hypoactivity in the Tg6799 mice and to test whether RU-505 treatment had a similar effect on a different strain of AD transgenic mice, we administered RU-505 to 4-mo-old TgCRND8 mice (Chishti et al., 2001) for 3 mo (analyzed at 7 mo-of-age) as a pilot experiment. During training, RU-505 treatment did not lead to improvement in spatial learning in TgCRND8 mice (Fig. 6 A); however, this treatment significantly reduced the latency to reach the target hole during the probe trial compared with vehicle-treated TgCRND8 mice (Fig. 6 B). Furthermore, the number of visits to the target hole during the probe trial was significantly higher in RU-505–treated TgCRND8 mice compared with vehicle-treated TgCRND8 mice (Fig. 6 C). In addition, vehicle-treated TgCRND8 mice showed similar locomotor activity during probe trials (Fig. 6 D), indicating that the impaired performance of vehicle-treated TgCRND8 mice in Barnes maze test is more likely caused by deficits in spatial memory. These results suggest that treatment of RU-505 substantially improved the deficits in spatial memory of TgCRND8 mice.

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