Lipoprotein lipase facilitates Aβ transport across the blood-brain barrier via LRP1: Validation of the obesity paradox in Alzheimer's disease.

INTRODUCTIONS: Being obese in mid-life is an increased risk of dementia and cognitive decline in late-life, while being obese in late-life is shown to be associated with a lower risk of these outcomes in some studies, which the above phenomenon is known as the "obesity paradox", however, the mechanisms underlying the phenomenon "obesity paradox" in Alzheimer's disease (AD) have not been clarified. Alterations in lipoprotein lipase (LPL) levels in adipose tissue and skeletal muscle are significant for individuals predisposed to obesity or those undergoing weight loss. LPL promotes the entry of low-density lipoprotein (LDL) into cells, which leads to the release of free cholesterol, influencing low-density lipoprotein receptor-related protein 1 (LRP1) levels. LRP1 located in brain microvascular endothelial cells plays a vital role in mediating intracerebral beta-amyloid protein (Aβ) trans-blood-brain barrier (BBB) transport. However, it is unknown whether LPL in peripheral tissues inhibits intracerebral Aβ trans-BBB transport via LRP1, and explains the observed "obesity paradox" in AD. OBJECTIVES: This study aims to investigate whether LPL in peripheral tissues contributes to the "obesity paradox" by regulating LRP1 expressed on brain microvascular endothelial cells in AD. METHODS: A population-based epidemiological case-control study, coupled with in vivo and in vitro experiments were adopted to elucidate the role of LPL in AD. RESULTS: A population-based epidemiological case-control study was adopted to elucidate the interaction between LPL alleles (rs285 and rs328) and apolipoprotein E4 (APOE4, the main risk gene for sporadic AD) promotes the occurrence and development of AD. We have adopted in vivo and in vitro experiments to elucidate LPL in adipose tissue influences the occurrence and development of AD by regulating LRP1 located in brain microvascular endothelial cells. CONCLUSION: These findings provide evidence that LPL plays a pivotal role in the pathogenesis of AD, and its variations in adipose tissue may explain the observed "obesity paradox" in AD.