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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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Administration of triptolide inhibited the activation of microglia and the release of proinflammatory factors. (A–C) Coronal sections of the three groups of mice indicated were stained for microglia with an antibody against Iba1 (immunohistochemical staining with DAB). (D–F) High magnification of Iba1 staining in the cortex area bracketed in A–C (upper box). (G–I) High magnification of Iba1 staining in the hippocampus bracketed in A–C (lower box). Arrows indicate Congo Red staining of senile neuritic plaques. The cortical (J) or hippocampal (K) area occupied by Iba1-positive microglia was quantified using Image Pro Plus 6.0 software. Meanwhile, frozen brain tissues were homogenized and ELISA analysis was used to measure the concentrations of TNFα (L,M) and IL-1β (N,O) in the cortex (Cor) and hippocampus (Hipp) of the three groups of mice. Concentrations were normalized to the brain wet weight in the hippocampus and cortex of all groups. The data are presented as means±s.e.m. n=6 animals per group, *P<0.05, **P<0.01, ***P<0.001 versus Tg+NS, one-way ANOVA with Tukey’s post hoc test. NS, normal saline; T10, triptolide. Scale bars: 500 μm (A–C); 50 μm (D–I).
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f6-0071385: Administration of triptolide inhibited the activation of microglia and the release of proinflammatory factors. (A–C) Coronal sections of the three groups of mice indicated were stained for microglia with an antibody against Iba1 (immunohistochemical staining with DAB). (D–F) High magnification of Iba1 staining in the cortex area bracketed in A–C (upper box). (G–I) High magnification of Iba1 staining in the hippocampus bracketed in A–C (lower box). Arrows indicate Congo Red staining of senile neuritic plaques. The cortical (J) or hippocampal (K) area occupied by Iba1-positive microglia was quantified using Image Pro Plus 6.0 software. Meanwhile, frozen brain tissues were homogenized and ELISA analysis was used to measure the concentrations of TNFα (L,M) and IL-1β (N,O) in the cortex (Cor) and hippocampus (Hipp) of the three groups of mice. Concentrations were normalized to the brain wet weight in the hippocampus and cortex of all groups. The data are presented as means±s.e.m. n=6 animals per group, *P<0.05, **P<0.01, ***P<0.001 versus Tg+NS, one-way ANOVA with Tukey’s post hoc test. NS, normal saline; T10, triptolide. Scale bars: 500 μm (A–C); 50 μm (D–I).

Mentions: Glial activation, part of an inflammatory response, is an important phenotype of AD brains (Selkoe, 2001). To determine the anti-inflammatory effect of triptolide in 5XFAD mice, the expression of the microglial marker Iba1 and the astrocyte marker GFAP was assessed by using immunohistochemical staining of brain sections from 5XFAD mice that had been treated with saline or triptolide. 5XFAD mice treated with saline exhibited microglial activation. These activated microglia were readily identified around the senile plaques, stained using Congo Red, by their thicker processes and more rounded cell bodies (Fig. 6E,H). The administration of triptolide for 8 weeks significantly inhibited activation of microglia (Fig. 6C,F,I) as more microglial cells exhibited the ramified morphology, similar to that of the wild-type mice that had been treated with saline (Fig. 6A,D,G). The area occupied by Iba1-positive microglia in the cortex and hippocampus of saline-treated 5XFAD mice was dramatically increased in association with Congo-red-stained neuritic plaques, whereas triptolide administration partially attenuated this increase (Fig. 6J,K). Compared with microglial activation, the GFAP-expressing hypertrophic astrocytes exhibited a widespread pattern in the cortex and hippocampus of 5XFAD mice treated with saline. This greater increase in GFAP-positive cells, corresponding to activated astrocytes, was found to be inhibited by triptolide administration (supplementary material Fig. S6). To quantitatively evaluate the inflammatory response in the brains of transgenic mice, we assessed the levels of the pro-inflammatory markers tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) in the cortex and hippocampus. ELISA data revealed that the concentrations of both TNFα and IL-1β were increased significantly in the hippocampus of transgenic mice, treatment with triptolide significantly attenuated this upregulation (Fig. 6L,N). However, there was no significant difference in the concentration of TNFα or IL-1β in the cortex of any of the treated groups (Fig. 6M,O), even though glial activation was observed. This suggests that the production of TNFα and IL-1β is an early and relatively transient process, rather than a prolonged and stable event, such as glial activation in the AD brain, because pathological alterations, including Aβ accumulation and glial activation, were first detected in the cortex of 5XFAD mice (Oakley et al., 2006).


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)

Administration of triptolide inhibited the activation of microglia and the release of proinflammatory factors. (A–C) Coronal sections of the three groups of mice indicated were stained for microglia with an antibody against Iba1 (immunohistochemical staining with DAB). (D–F) High magnification of Iba1 staining in the cortex area bracketed in A–C (upper box). (G–I) High magnification of Iba1 staining in the hippocampus bracketed in A–C (lower box). Arrows indicate Congo Red staining of senile neuritic plaques. The cortical (J) or hippocampal (K) area occupied by Iba1-positive microglia was quantified using Image Pro Plus 6.0 software. Meanwhile, frozen brain tissues were homogenized and ELISA analysis was used to measure the concentrations of TNFα (L,M) and IL-1β (N,O) in the cortex (Cor) and hippocampus (Hipp) of the three groups of mice. Concentrations were normalized to the brain wet weight in the hippocampus and cortex of all groups. The data are presented as means±s.e.m. n=6 animals per group, *P<0.05, **P<0.01, ***P<0.001 versus Tg+NS, one-way ANOVA with Tukey’s post hoc test. NS, normal saline; T10, triptolide. Scale bars: 500 μm (A–C); 50 μm (D–I).
© Copyright Policy - open-access
Related In: Results  -  Collection

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f6-0071385: Administration of triptolide inhibited the activation of microglia and the release of proinflammatory factors. (A–C) Coronal sections of the three groups of mice indicated were stained for microglia with an antibody against Iba1 (immunohistochemical staining with DAB). (D–F) High magnification of Iba1 staining in the cortex area bracketed in A–C (upper box). (G–I) High magnification of Iba1 staining in the hippocampus bracketed in A–C (lower box). Arrows indicate Congo Red staining of senile neuritic plaques. The cortical (J) or hippocampal (K) area occupied by Iba1-positive microglia was quantified using Image Pro Plus 6.0 software. Meanwhile, frozen brain tissues were homogenized and ELISA analysis was used to measure the concentrations of TNFα (L,M) and IL-1β (N,O) in the cortex (Cor) and hippocampus (Hipp) of the three groups of mice. Concentrations were normalized to the brain wet weight in the hippocampus and cortex of all groups. The data are presented as means±s.e.m. n=6 animals per group, *P<0.05, **P<0.01, ***P<0.001 versus Tg+NS, one-way ANOVA with Tukey’s post hoc test. NS, normal saline; T10, triptolide. Scale bars: 500 μm (A–C); 50 μm (D–I).
Mentions: Glial activation, part of an inflammatory response, is an important phenotype of AD brains (Selkoe, 2001). To determine the anti-inflammatory effect of triptolide in 5XFAD mice, the expression of the microglial marker Iba1 and the astrocyte marker GFAP was assessed by using immunohistochemical staining of brain sections from 5XFAD mice that had been treated with saline or triptolide. 5XFAD mice treated with saline exhibited microglial activation. These activated microglia were readily identified around the senile plaques, stained using Congo Red, by their thicker processes and more rounded cell bodies (Fig. 6E,H). The administration of triptolide for 8 weeks significantly inhibited activation of microglia (Fig. 6C,F,I) as more microglial cells exhibited the ramified morphology, similar to that of the wild-type mice that had been treated with saline (Fig. 6A,D,G). The area occupied by Iba1-positive microglia in the cortex and hippocampus of saline-treated 5XFAD mice was dramatically increased in association with Congo-red-stained neuritic plaques, whereas triptolide administration partially attenuated this increase (Fig. 6J,K). Compared with microglial activation, the GFAP-expressing hypertrophic astrocytes exhibited a widespread pattern in the cortex and hippocampus of 5XFAD mice treated with saline. This greater increase in GFAP-positive cells, corresponding to activated astrocytes, was found to be inhibited by triptolide administration (supplementary material Fig. S6). To quantitatively evaluate the inflammatory response in the brains of transgenic mice, we assessed the levels of the pro-inflammatory markers tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) in the cortex and hippocampus. ELISA data revealed that the concentrations of both TNFα and IL-1β were increased significantly in the hippocampus of transgenic mice, treatment with triptolide significantly attenuated this upregulation (Fig. 6L,N). However, there was no significant difference in the concentration of TNFα or IL-1β in the cortex of any of the treated groups (Fig. 6M,O), even though glial activation was observed. This suggests that the production of TNFα and IL-1β is an early and relatively transient process, rather than a prolonged and stable event, such as glial activation in the AD brain, because pathological alterations, including Aβ accumulation and glial activation, were first detected in the cortex of 5XFAD mice (Oakley et al., 2006).

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