Zeng, Y; Zhang, J; Zhu, Y; Zhang, J; Shen, H; Lu, J; Pan, X; Lin, N; Dai, X; Zhou, M; Chen, X
Alzheimer's disease (AD) is characterized by early impairments in memory and progressive neurodegeneration. Disruption of synaptic plasticity processes that underlie learning and memory contribute partly to this pathophysiology. Tripchlorolide (T4), an extract from a traditional Chinese herbal Tripterygium wilfordii Hook F, has been shown to be neuroprotective in animal models of Parkinson's disease and to improve cognitive deficits in senescence-accelerated mouse P8. In this study, we investigated the effect of T4 on cognitive decline and synaptic plasticity in five times familial AD (5XFAD) mice co-expressing mutated amyloid precursor protein and presenilin-1. Five-month-old 5XFAD mice and wild type littermates were intraperitoneally injected with T4, 5 μg/kg or 25 μg/kg, every other day for 60 days. T4 treatment significantly improved spatial learning and memory, alleviated synaptic ultrastructure degradation, up-regulated expression of synapse-related proteins, including synaptophysin, post-synaptic density-95, N-methyl-D-aspartate receptor subunit 1, phosphorylation of calcium/calmodulin dependent protein kinase II α, and phosphorylation of cyclic AMP-response element binding protein, and promoted activation of the phophoinositide-3-kinase-Akt-mammalian target of rapamycin signaling pathway in 5XFAD mice. Accumulation of amyloid β (Aβ) may contribute to synapse dysfunction and memory impairment in AD. We found that T4 treatment significantly reduced cerebral Aβ deposits and lowered Aβ levels in brain homogenates. These effects coincided with a reduction in cleavage of β-carboxyl-terminal amyloid precursor protein (APP) fragment, levels of soluble APPβ, and protein expression of β-site APP cleaving enzyme 1. Taken together, our findings identify T4 as a potent negative regulator of brain Aβ levels and show that it significantly ameliorates synaptic degeneration and cognitive deficits in a mouse model of AD. Tripchlorolide (T4), a traditional Chinese herbal compound, was shown to be neuroprotective, but the underlying mechanisms remain unclear. The present study demonstrates that T4 alleviates cognitive decline in five times familial AD (5XFAD) mice. T4 acts against cognition impairment through downregulating BACE1 activity, reducing Aβ deposits, upregulating synapse-related proteins expression, in particular the PI3K-Akt-mTOR signaling pathway. The findings suggest that T4 may be a promising novel therapeutic option for treating AD. Akt = protein kinase B; Aβ = amyloid β; AD = AlzheimeÅs disease; BACE1 = beta-secretase 1; PI3K = phosphatidylinositol 3-kinase; mTOR = mammalian target of rapamycin Tripchlorolide (T4), a traditional Chinese herbal compound, was shown to be neuroprotective, but the underlying mechanisms remain unclear. The present study demonstrates that T4 alleviates cognitive decline in five times familial AD (5XFAD) mice. T4 acts against cognition impairment through downregulating BACE1 activity, reducing Aβ deposits, upregulating synapse-related proteins expression, in particular the PI3K-Akt-mTOR signaling pathway. The findings suggest that T4 may be a promising novel therapeutic option for treating AD. Akt = protein kinase B; Aβ = amyloid β; AD = AlzheimeÅs disease; BACE1 = beta-secretase 1; PI3K = phosphatidylinositol 3-kinase; mTOR = mammalian target of rapamycin © 2015 International Society for Neurochemistry.
