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.