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. Fivemonth-old 5XFAD mice and wild type littermates were intraperitoneally injected with T 4 , 5 lg/kg or 25 lg/kg, every other day for 60 days. 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 a, 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 b (Ab) may contribute to synapse dysfunction and memory impairment in AD. We found that T 4 treatment significantly reduced cerebral Ab deposits and lowered Ab levels in brain homogenates. These effects coincided with a reduction in cleavage of b-carboxyl-terminal amyloid precursor protein (APP) fragment, levels of soluble APPb, and protein expression of b-site APP cleaving enzyme 1. Taken together, our findings identify T 4 as a potent negative regulator of brain Ab levels and show that it significantly ameliorates synaptic degeneration and cognitive deficits in a mouse model of AD. Keywords: Alzheimer's disease, amyloid b, cognition, synaptic plasticity, transgenic mice, tripchlorolide. Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide, and the main clinical manifestation is chronic, progressive worsening of cognitive function. Its incidence is directly linked to aging, and as life Received July 17, 2014; revised manuscript received January 21, 2015; accepted January 22, 2015.Address correspondence and reprint requests to Xiaochun Chen, Department of Neurology and Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China. E-mail: chenxc998@163.com 1 These authors contributed equally to this work.Abbreviations used: 5XFAD, five times familial AD; AD, Alzheimer's disease; ADAM, a disintegrin and metalloprotease; Akt, serine threonine Kinase; APP, amyloid precursor protein; Ab, amyloid b; BACE, b-site amyloid precursor protein cleavage enzyme; CaMKII, calcium/calmodulin-dependent protein kinase II; CREB, cyclic AMP-response element binding protein; CTF, carboxyl-terminal fragment; DMSO, dimethylsulp...