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Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy.
Neuropharmacology 2018 March 2
Alzheimer's disease (AD) is a progressively neurodegenerative disease with typical hallmarks of amyloid β (Aβ) plaque accumulation, neurofibrillary tangle (NFT) formation and neuronal death extension. Aggressive Aβ accumulation promotes senile plaque formation and perturbs endoplasmic reticulum (ER) function to trigger the unfolded protein response (UPR) leading to neuronal apoptosis. The stress-dependent activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) increases the phosphorylation of eukaryotic translation initiation factor-2α (eIF2α) to promote the preferential synthesis of β-site APP cleavage enzyme 1 (BACE1) and Aβ generation in turn. Additionally, dysfunction in autophagy has been reported to contribute to several neurodegenerative diseases including AD, and impairment in autophagy-mediated pathway may constitutively stimulate the generation of Aβ in AD. Here we discovered that protopanaxadiol derivative 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopanaxadiol-3β-yl)-urea (DDPU) effectively improved the activity of daily living (ADL) and cognitive deficits in APP/PS1 transgenic mice. The crosstalk between Aβ and ER stress has been intensively investigated by using DDPU as a probe. DDPU reduced Aβ production mainly by inhibiting the PERK/eIF2α signaling-mediated BACE1 translation and stimulated Aβ clearance by promoting autophagy as a PI3 K inhibitor through PI3 K/AKT/mTOR signaling pathway, while exhibited neuroprotective effect involving attenuation of ER stress. DDPU might be the first reported ginsenoside derivative with dual effects on both autophagy promotion and ER stress amelioration. Our results have highlighted the potential of DDPU in the treatment of AD.
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