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Triptolide treatment reduces Alzheimer's disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD.

Wang Q, Xiao B, Cui S, Song H, Qian Y, Dong L, An H, Cui Y, Zhang W, He Y, Zhang J, Yang J, Zhang F, Hu G, Gong X, Yan Z, Zheng Y, Wang X - Dis Model Mech (2014)

Bottom Line: We observed enhanced spatial learning performances, and attenuated Aβ production and deposition in the brain.Triptolide also inhibited the processing of amyloidogenic APP, as well as the expression of βAPP-cleaving enzyme-1 (BACE1) both in vivo and in vitro.In addition, triptolide exerted anti-inflammatory and anti-oxidative effects on the transgenic mouse brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Department of Neurobiology, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, PR China. Beijing Institute for Brain Disorders, Beijing 100069, PR China.

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Chronic administration of triptolide improved the spatial memory of 5XFAD mice in the Morris water maze. (A) Treatment schedule for the experiment. i.p., intraperitoneal. (B) The escape strategy during the hidden platform task adopted by saline-treated wild-type mice (WT+NS), saline-treated 5XFAD mice (Tg+NS) and triptolide (T10)-treated 5XFAD mice (Tg+T10) was detected by using a camera. (C) The escape latency of these three groups of mice to find the hidden platform was recorded on every training day. (D,E) One day after finishing the acquisition task, a probe trial was performed to evaluate spatial memory. The platform quadrant crossing time (D), and the time required for the first crossing over the platform site (E), were used to determine the memory retention of these three groups of mice. All values represent mean±s.e.m.; n=8–10 animals per group. *P<0.05, **P<0.01 versus Tg+NS, samples were compared using one-way ANOVA with Tukey’s post hoc test. NS, normal saline.
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f2-0071385: Chronic administration of triptolide improved the spatial memory of 5XFAD mice in the Morris water maze. (A) Treatment schedule for the experiment. i.p., intraperitoneal. (B) The escape strategy during the hidden platform task adopted by saline-treated wild-type mice (WT+NS), saline-treated 5XFAD mice (Tg+NS) and triptolide (T10)-treated 5XFAD mice (Tg+T10) was detected by using a camera. (C) The escape latency of these three groups of mice to find the hidden platform was recorded on every training day. (D,E) One day after finishing the acquisition task, a probe trial was performed to evaluate spatial memory. The platform quadrant crossing time (D), and the time required for the first crossing over the platform site (E), were used to determine the memory retention of these three groups of mice. All values represent mean±s.e.m.; n=8–10 animals per group. *P<0.05, **P<0.01 versus Tg+NS, samples were compared using one-way ANOVA with Tukey’s post hoc test. NS, normal saline.

Mentions: According to the behavioral phenotype, we selected 5-month-old 5XFAD mice, which had shown deficits in learning and memory, to assess the therapeutic effects of triptolide (20 μg/kg of body weight, treated for 8 weeks) on the symptomatic AD model. The behavioral performance of mice was determined at 7 months old (Fig. 2A). As shown in Fig. 2B, the escape pathway on the fifth day of training that was adopted by the 5XFAD mice treated with saline in the hidden platform task was more complicated and longer than that used by control mice treated with saline. Importantly, the behavioral impairment could be rescued upon treatment with triptolide. The escape latency of 5XFAD mice to find the hidden platform was longer than that of controls on day 4 and 5 of training, whereas the triptolide-treated 5XFAD mice demonstrated an improved learning ability in the spatial learning task compared with saline-treated 5XFAD mice (Fig. 2C). However, compared with wild-type control mice, both saline- and triptolide-treated 5XFAD mice spent significantly less time in the target quadrant (Fig. 2D) and took more time to find the quadrant that had originally contained the platform (Fig. 2E) during the probe trial, which was performed 24 hours after the last training session in the hidden platform task. This suggests that triptolide prevented the deterioration of learning ability but did not improve the memory retention of 5XFAD mice. Meanwhile, we also monitored the side effects of triptolide (20 μg/kg of body weight intraperitoneally for 8 weeks) on peripheral tissues of these mice and did not find any toxicity in a wide variety of tissues, including the heart, liver, spleen, lung and kidney (supplementary material Fig. S2). Moreover, treatment with triptolide did not affect the body weight of the 5XFAD mice (supplementary material Fig. S3).


Triptolide treatment reduces Alzheimer's disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD.

Wang Q, Xiao B, Cui S, Song H, Qian Y, Dong L, An H, Cui Y, Zhang W, He Y, Zhang J, Yang J, Zhang F, Hu G, Gong X, Yan Z, Zheng Y, Wang X - Dis Model Mech (2014)

Chronic administration of triptolide improved the spatial memory of 5XFAD mice in the Morris water maze. (A) Treatment schedule for the experiment. i.p., intraperitoneal. (B) The escape strategy during the hidden platform task adopted by saline-treated wild-type mice (WT+NS), saline-treated 5XFAD mice (Tg+NS) and triptolide (T10)-treated 5XFAD mice (Tg+T10) was detected by using a camera. (C) The escape latency of these three groups of mice to find the hidden platform was recorded on every training day. (D,E) One day after finishing the acquisition task, a probe trial was performed to evaluate spatial memory. The platform quadrant crossing time (D), and the time required for the first crossing over the platform site (E), were used to determine the memory retention of these three groups of mice. All values represent mean±s.e.m.; n=8–10 animals per group. *P<0.05, **P<0.01 versus Tg+NS, samples were compared using one-way ANOVA with Tukey’s post hoc test. NS, normal saline.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257007&req=5

f2-0071385: Chronic administration of triptolide improved the spatial memory of 5XFAD mice in the Morris water maze. (A) Treatment schedule for the experiment. i.p., intraperitoneal. (B) The escape strategy during the hidden platform task adopted by saline-treated wild-type mice (WT+NS), saline-treated 5XFAD mice (Tg+NS) and triptolide (T10)-treated 5XFAD mice (Tg+T10) was detected by using a camera. (C) The escape latency of these three groups of mice to find the hidden platform was recorded on every training day. (D,E) One day after finishing the acquisition task, a probe trial was performed to evaluate spatial memory. The platform quadrant crossing time (D), and the time required for the first crossing over the platform site (E), were used to determine the memory retention of these three groups of mice. All values represent mean±s.e.m.; n=8–10 animals per group. *P<0.05, **P<0.01 versus Tg+NS, samples were compared using one-way ANOVA with Tukey’s post hoc test. NS, normal saline.
Mentions: According to the behavioral phenotype, we selected 5-month-old 5XFAD mice, which had shown deficits in learning and memory, to assess the therapeutic effects of triptolide (20 μg/kg of body weight, treated for 8 weeks) on the symptomatic AD model. The behavioral performance of mice was determined at 7 months old (Fig. 2A). As shown in Fig. 2B, the escape pathway on the fifth day of training that was adopted by the 5XFAD mice treated with saline in the hidden platform task was more complicated and longer than that used by control mice treated with saline. Importantly, the behavioral impairment could be rescued upon treatment with triptolide. The escape latency of 5XFAD mice to find the hidden platform was longer than that of controls on day 4 and 5 of training, whereas the triptolide-treated 5XFAD mice demonstrated an improved learning ability in the spatial learning task compared with saline-treated 5XFAD mice (Fig. 2C). However, compared with wild-type control mice, both saline- and triptolide-treated 5XFAD mice spent significantly less time in the target quadrant (Fig. 2D) and took more time to find the quadrant that had originally contained the platform (Fig. 2E) during the probe trial, which was performed 24 hours after the last training session in the hidden platform task. This suggests that triptolide prevented the deterioration of learning ability but did not improve the memory retention of 5XFAD mice. Meanwhile, we also monitored the side effects of triptolide (20 μg/kg of body weight intraperitoneally for 8 weeks) on peripheral tissues of these mice and did not find any toxicity in a wide variety of tissues, including the heart, liver, spleen, lung and kidney (supplementary material Fig. S2). Moreover, treatment with triptolide did not affect the body weight of the 5XFAD mice (supplementary material Fig. S3).

Bottom Line: We observed enhanced spatial learning performances, and attenuated Aβ production and deposition in the brain.Triptolide also inhibited the processing of amyloidogenic APP, as well as the expression of βAPP-cleaving enzyme-1 (BACE1) both in vivo and in vitro.In addition, triptolide exerted anti-inflammatory and anti-oxidative effects on the transgenic mouse brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Department of Neurobiology, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, PR China. Beijing Institute for Brain Disorders, Beijing 100069, PR China.

Show MeSH
Related in: MedlinePlus