期刊
JOURNAL OF NEUROCHEMISTRY
卷 133, 期 1, 页码 38-52出版社
WILEY
DOI: 10.1111/jnc.13056
关键词
Alzheimer's disease; amyloid; cognition; synaptic plasticity; transgenic mice; tripchlorolide
资金
- National Natural Science Foundation of China [81171216, 91232709, 81071007]
- Major Project of Fujian Science and Technology Bureau [2009D061]
- Fujian Province Natural Science Fund for distinguished young scholars [2009J06015]
- National and Fujian Province's Key Clinical Specialty Discipline Construction Programs
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 (T-4), 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 T-4 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 T-4, 5g/kg or 25g/kg, every other day for 60days. T-4 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 , 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 (A) may contribute to synapse dysfunction and memory impairment in AD. We found that T-4 treatment significantly reduced cerebral A deposits and lowered A levels in brain homogenates. These effects coincided with a reduction in cleavage of -carboxyl-terminal amyloid precursor protein (APP) fragment, levels of soluble APP, and protein expression of -site APP cleaving enzyme 1. Taken together, our findings identify T-4 as a potent negative regulator of brain A levels and show that it significantly ameliorates synaptic degeneration and cognitive deficits in a mouse model of AD.
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