Single-cell Data Unveil the Multifaceted Role of LRP1 in Alzheimer’s Disease Pathogenesis

Abstract

Abstract Background The role of low-density lipoprotein receptor-related protein 1 (LRP1) in Alzheimer’s disease (AD) has been a focal point of research, highlighting its crucial function in amyloid-beta (Aβ) metabolism in the central nervous system. Despite these significant findings, the detailed mechanisms of LRP1 in neuronal Aβ handling and its systemic effects in AD have not been fully elucidated. Here, we employ innovative single-cell data analysis and temporal analysis complemented by multi-tissue data integration to shed light on the specific roles and systemic impact of LRP1 in AD. Methods We conducted in-depth single-cell data mining and analysis using publicly available datasets from the GSE181279, GSE174367, and GSE173429. These findings were augmented with complementary in vivo and in vitro experiments aimed at substantiating the function of LRP1 in the phagocytosis of Aβ by hepatic macrophages. Results Detailed data mining and analysis of public datasets have revealed the nuanced role of LRP1 in AD, notably impacting the brain, blood, and liver. Our findings demonstrated pronounced upregulation of LRP1 in brain astrocyte, microglia, and oligodendrocyte progenitor cells (OPCs), establishing a direct correlation with the neurological manifestations of AD. In peripheral blood mononuclear cells (PBMC), LRP1 exhibited unique expression patterns, underscoring its systemic influence on AD pathology. Critically, our data reveal that physical exercise modulates LRP1 expression in Kupffer cells, identifying lifestyle factors as key modulators of the molecular processes involved in AD. Experimental evidence further confirms that reduced LRP1 expression is associated with impaired amyloid-beta clearance, highlighting its pivotal role in the progression of AD. Collectively, these insights position LRP1 as a central molecular player in AD, suggesting novel avenues for therapeutic intervention. Conclusions This study, which involved leveraging multi-tissue single-cell analyses of human and mice samples, investigated the multifaceted functionality and molecular dynamics of LRP1 in AD progression. Additionally, this study unveiled the modulatory effects of physical exercise on LRP1 expression, paving the way for novel therapeutic approaches for AD management.