Establishment and phenotypic analysis of an APP/PS1 mouse model with hepatic Kupffer cell depletion
CHEN Shasha
LI Ziyue
SHI Jiayi
SONG Yuzhe
QIU Mangmang
GOU Xingchun
Abstract：Objective To establish an APP/PS1 mouse model with hepatic Kupffer cell depletion,systematically analyze the phenotypic changes of the model in terms of Alzheimer's disease(AD)cognitive function,brain AD pathological characteristics,liver function and inflammation,and provide an experimental basis for exploring the association between Kupffer cells and the pathogenesis of AD.Methods APP/PS1 double-transgenic AD mice were used to construct an APP/PS1 mouse model with Kupffer cell depletion by intraperitoneal injection of clodronate;cognitive function was evaluated by Morris water maze;thioflavin S staining and immunohistochemistry(labeled with 6E10 antibody)were used to detect amyloid-beta(Aβ)deposition in the brain;the expression of glial fibrillary acidic protein(astrocyte activation marker)and ionized calcium-binding adapter molecule 1(microglial activation marker)in the brain were detected by means of immunohistochemistry;hepatic tissue immunofluorescence and serum detection were used to analyze peripheral Aβ metabolism;Western blotting was used to analyze the expression level of low-density lipoprotein receptor-related protein 1(LRP-1)in hepatic tissue;ELISA was used to detect the levels of liver function indicators in serum and inflammatory cytokines in liver tissue.Results Kupffer cell depletion exacerbated spatial memory impairment and increased Aβ deposition(P＜0.05),as well as astrocyte and microglial activation in the cortex and hippocampus of APP/PS1 mice(P＜0.05);increased Aβ deposition in liver tissue(P＜0.01),significantly elevated serum Aβ40 and Aβ42 levels(P＜0.01),and upregulated expression level of LRP-1—the primary receptor for hepatic clearance of Aβ(P＜0.01).Kupffer cell depletion had no significant effect on liver function of APP/PS1 mice(P＞0.05),but could inhibit liver inflammation(P＜0.05).Conclusion We successfully established an APP/PS1 mouse model with hepatic Kupffer cell depletion.This model exhibited more severe AD pathological features and cognitive impairment,revealing that hepatic Kupffer cells can be involved in the pathological process of AD by regulating peripheral Aβ clearance.
Keywords：Alzheimer's diseaseliverKupffer cellsAPP/PS1 miceamyloid-betamodel establishmentphenotypic analysislow-density lipoprotein receptor-related protein 1
Publication Date：2026-07-31
Online Publishing Date：2026-08-26(First online date of this platform, not the publication date of the document)
Pages：9( 1008-1016 )