Triptolide treatment reduces Alzheimer's disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD.
Bottom Line: Triptolide is the major active compound extracted from Tripterygium wilfordii Hook.f., a traditional Chinese medicinal herb that is commonly used to treat inflammatory diseases.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.
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
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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).
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.