This study examined the effect of curcumin on pathological manifestations and clearance of amyloid β peptide (Aβ) in the hippocampus of 8-month-old transgenic APP/PS1 mice with inherent Alzheimer's disease. APP/PS1 mice and the age-matched wild-type controls were subjected to 3 behavioral tests: open field, new object recognition, and Morris water maze. Expression of Aβ, APP, CTF, BACE1, IDE, NEP, and LRP1 proteins in the extracted hippocampal tissue was evaluated by Western blotting. The distribution and the quantity of amyloid plaques and the spread of microglia in the hippocampus were determined by immunofluorescence. The contents of Aβ40 and Aβ42 in the hippocampus were assayed and analyzed on Simoa HD-1 analyzer. The proteins interacting with Aβ in the hippocampus of APP/PS1 mice were detected by co-immunoprecipitation. Curcumin significantly reduced motor hyperactivity in the open-field test, improved short-term recognition memory, spatial learning, and reference memory in APP/PS1 mice. In the hippocampus of APP/PS1 mice, curcumin significantly diminished the elevated Aβ levels and inhibited microglia proliferation. At the same time, curcumin had no effect on Aβ production, extracellular enzymatic hydrolysis, and LRP1-mediated outward transport, but enhanced Aβ clearance by activation of the intracellular ubiquitin-proteasome system and related peripheral mechanisms. Thus, curcumin improves the learning and memory abilities of APP/PS1 mice and reduces the pathological accumulation of Aβ in the brain.© 2023. Springer Science+Business Media, LLC, part of Springer Nature.