This study investigates the neuroprotective properties of berberine (a natural isoquinoline alkaloid isolated from the Rhizoma coptidis) and finds that berberine could promote beta-amyloid (A beta) clearance and inhibit A beta production in the triple-transgenic mouse model of Alzheimer's disease (3 x Tg-AD). During the study, berberine was first administrated to treat 3 x Tg-AD mice and primary neurons. Morris water maze assay, western blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining and histological analysis, transmission electron microscopic analysis were then used to evaluate the effects of the berberine administration. The result showed that berberine significantly improved 3 x Tg-AD mice's spatial learning capacity and memory retention, promoted autophagy activity identified by the enhancement of brain LO-II, beclin-1, hVps34, and Cathepsin-D levels as well as the reduction of brain P62 and Bcl-2 levels in AD mice, facilitated reduction of AV, and APP levels, reduced A beta plaque deposition in the hippocampus of AD mice, and inhibited b-site APP cleavage enzyme 1 (BACE1) expression. Similar results were also found in 3 x Tg-AD primary hippocampal neurons: berbernine treatment decreased the levels of extracellular and intracellular A beta 1-42, increased the protein levels of 10-11, beclin-1, hVps34, and Cathepsin-D, and decreased the levels of P62. Bcl-2, APP and BACE1 levels. In summary, berberine shows neuroprotective effects on 3 x Tg-AD mice and may be a promising multitarget drug in the preventionand protection against AD. (C) 2017 Published by Elsevier Inc.