Laboratory for Experimental Mouse Genetics, Department of Human Genetics, KU Leuven, Herestraat 49, Box 604, 3000, Leuven, Belgium.
Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany.
Mol Neurobiol. 2019 Oct;56(10):7234-7245. doi: 10.1007/s12035-019-1594-2. Epub 2019 Apr 19.
The low-density lipoprotein receptor-related protein-1 (LRP1) has a dual role in the metabolism of the amyloid precursor protein (APP). In cellular models, LRP1 enhances amyloid-β (Aβ) generation via APP internalization and thus its amyloidogenic processing. However, conditional knock-out studies in mice define LRP1 as an important mediator for the clearance of extracellular Aβ from brain via cellular degradation or transcytosis across the blood-brain barrier (BBB). In order to analyze the net effect of LRP1 on production and clearance of Aβ in vivo, we crossed mice with impaired LRP1 function with a mouse model of Alzheimer's disease (AD). Analysis of Aβ metabolism showed that, despite reduced Aβ clearance due to LRP1 inactivation in vivo, less Aβ was found in cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Further analysis of APP metabolism revealed that impairment of LRP1 in vivo shifted APP processing from the Aβ-generating amyloidogenic cleavage by beta-secretase to the non-amyloidogenic processing by alpha-secretase as shown by a decrease in extracellular Aβ and an increase of soluble APP-α (sAPP-α). This shift in APP processing resulted in overall lower Aβ levels and a reduction in plaque burden. Here, we present for the first time clear in vivo evidence that global impairment of LRP1's endocytosis function favors non-amyloidogenic processing of APP due to its reduced internalization and subsequently, reduced amyloidogenic processing. By inactivation of LRP1, the inhibitory effect on Aβ generation overrules the simultaneous impaired Aβ clearance, resulting in less extracellular Aβ and reduced plaque deposition in a mouse model of AD.
低密度脂蛋白受体相关蛋白-1（LRP1）在淀粉样前体蛋白（APP）的代谢中具有双重作用。在细胞模型中，LRP1 通过 APP 的内化增强了淀粉样β（Aβ）的生成，从而促进了其淀粉样形成过程。然而，条件性敲除小鼠研究将 LRP1 定义为通过细胞降解或穿过血脑屏障（BBB）的转胞吞作用从大脑中清除细胞外 Aβ 的重要介质。为了分析 LRP1 对体内 Aβ产生和清除的净效应，我们将 LRP1 功能受损的小鼠与阿尔茨海默病（AD）的小鼠模型进行了杂交。对 Aβ代谢的分析表明，尽管由于 LRP1 在体内失活导致 Aβ清除减少，但脑脊液（CSF）和脑间质液（ISF）中的 Aβ 含量减少。进一步分析 APP 代谢表明，LRP1 在体内的损伤导致 APP 加工从β-分泌酶产生 Aβ的淀粉样形成裂解向非淀粉样形成的 α-分泌酶裂解转移，表现为细胞外 Aβ减少和可溶性 APP-α（sAPP-α）增加。APP 加工的这种转变导致 Aβ 水平总体降低和斑块负担减少。在这里，我们首次提供了明确的体内证据，表明 LRP1 内吞作用的整体功能障碍有利于 APP 的非淀粉样形成加工，因为其内化减少，随后淀粉样形成加工减少。通过 LRP1 的失活，对 Aβ生成的抑制作用超过了同时受损的 Aβ清除，导致 AD 小鼠模型中细胞外 Aβ减少和斑块沉积减少。
