ABSTRACT
OBJECTIVE To explore the potential effect and mechanisms of protopanaxadiol deriva-tive 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopa- naxadiol-3b-yl)-urea (DDPU) in the treatment of Alzheimer disease.METHODS ELISA assay was performed in both HEK293-APPswe and CHO-APP cells to demonstrate the efficacy of DDPU in reducing Ab level.SH-SY5Y,primary neurons and astrocyte cellswereused to study the regulation of DDPU against the signaling pathways involved in Aβ/ER-stress pathology. APP/PS1 transgenic mice wereusedto study the regulation of DDPU against ADL and cognitive deficits. APP/PS1 transgenic mice were randomly placed into three groups (n=10):The two 6-month transgenic groups were administrated with 30 mg·kg-1DDPU or vehicle and the 6-month non-transgenic group was administrated with vehicle for 100 days by intraperitonealinjec-tion.After 100-day administration,nest construction assay and Morris water maze(MWM)assay were applied to evaluate the daily living activities and cognitive abilities of the mice with continuous DDPU treatment. Upon completion of behavior assays, mice were euthanized, and the brains were removed and bisected in mid-sagittal plane.The right hemispheres were frozen and stored at-80°C,and the left hemispheres were fixed in 4% paraformaldehyde. RESULTS DDPU effectively improved learning and memory impairments in APP/PS1 transgenic mice, and the underlying mechanisms have been inten-sively investigated. DDPU reduced Ab production by inhibiting the PERK/eIF2a signaling-mediated BACE1 translation, while promoted Ab clearance as a PI3K inhibitor thus negatively regulating PI3K/AKT/mTOR signaling in promotion of autophagy.Moreover,DDPU also exhibited neuroprotective effect by attenuating ER stress. Therefore, all findings have clearly demonstrated the crosstalk between Ab and ER stress, and confirmed that targeting ER stress should be a potential target for innovative anti-AD drug development,while highlighted the potential of DDPU in the treatment of AD.