Amyloid-beta (A beta) is the major component of senile plaques in Alzheimer's disease (AD) brains. Senile plaques are generally observed in cerebral cortex (CTX) rather than cerebellum (CBL) in AD patients. However, it is not clear why CBL has less A beta deposition than CTX. It is very important to elucidate the mechanism of suppressing A beta deposition in CBL, because it contributes to understanding of not only AD pathogenesis but also prevention and cure of AD. In this study, we explored to figure out the potential mechanism of reducing A beta deposition in CBL. We observed higher age-dependent elevation of A beta level in CTX rather than CBL of human APP knock-in AD model mice, although we detected no significant differences in the levels of interstitial fluid A beta in these brain tissues. These data imply that less A beta deposition in CBL is due to enhanced A beta clearance rather than altered A beta production in CBL. To gain insights into A beta clearance in CBL, we injected fluorescence-labeled A beta in brain tissues. Importantly diffusion area of fluorescent A beta in CBL was roughly six-times larger than that in CTX within 2 h of injection. In addition, injected A beta area in CBL decreased sharply after 24 h and CBL-injected A beta was robustly detected in deep cervical lymph nodes (DcLNs). In contrast, diffusion area of fluorescent A beta in CTX was consistent up to 72 h and CTX-injected A beta was faintly detected in DcLNs. Our data suggest that enhanced A beta drainage in association with meningeal lymphatic system is responsible for less A beta deposition in CBL. (C) 2020 Elsevier Inc. All rights reserved.