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Amyloid-beta impairs insulin signaling by accelerating autophagy-lysosomal degradation of LRP-1 and IR-β in blood-brain barrier endothelial cells in vitro and in 3XTg-AD mice.
Molecular and Cellular Neuroscience ( IF 2.6 ) Pub Date : 2019-07-02 , DOI: 10.1016/j.mcn.2019.103390 Chaitanya Chakravarthi Gali 1 , Elham Fanaee-Danesh 1 , Martina Zandl-Lang 1 , Nicole Maria Albrecher 1 , Carmen Tam-Amersdorfer 1 , Anika Stracke 1 , Vinay Sachdev 2 , Florian Reichmann 3 , Yidan Sun 1 , Afrim Avdili 1 , Marielies Reiter 1 , Dagmar Kratky 4 , Peter Holzer 3 , Achim Lass 5 , Karunya K Kandimalla 6 , Ute Panzenboeck 7
Molecular and Cellular Neuroscience ( IF 2.6 ) Pub Date : 2019-07-02 , DOI: 10.1016/j.mcn.2019.103390 Chaitanya Chakravarthi Gali 1 , Elham Fanaee-Danesh 1 , Martina Zandl-Lang 1 , Nicole Maria Albrecher 1 , Carmen Tam-Amersdorfer 1 , Anika Stracke 1 , Vinay Sachdev 2 , Florian Reichmann 3 , Yidan Sun 1 , Afrim Avdili 1 , Marielies Reiter 1 , Dagmar Kratky 4 , Peter Holzer 3 , Achim Lass 5 , Karunya K Kandimalla 6 , Ute Panzenboeck 7
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Aberrant insulin signaling constitutes an early change in Alzheimer's disease (AD). Insulin receptors (IR) and low-density lipoprotein receptor-related protein-1 (LRP-1) are expressed in brain capillary endothelial cells (BCEC) forming the blood-brain barrier (BBB). There, insulin may regulate the function of LRP-1 in Aβ clearance from the brain. Changes in IR-β and LRP-1 and insulin signaling at the BBB in AD are not well understood. Herein, we identified a reduction in cerebral and cerebrovascular IR-β levels in 9-month-old male and female 3XTg-AD (PS1M146V, APPSwe, and tauP301L) as compared to NTg mice, which is important in insulin mediated signaling responses. Reduced cerebral IR-β levels corresponded to impaired insulin signaling and LRP-1 levels in brain. Reduced cerebral and cerebrovascular IR-β and LRP-1 levels in 3XTg-AD mice correlated with elevated levels of autophagy marker LC3B. In both genotypes, high-fat diet (HFD) feeding decreased cerebral and hepatic LRP-1 expression and elevated cerebral Aβ burden without affecting cerebrovascular LRP-1 and IR-β levels. In vitro studies using primary porcine (p)BCEC revealed that Aβ peptides 1-40 or 1-42 (240 nM) reduced cellular levels and interaction of LRP-1 and IR-β thereby perturbing insulin-mediated signaling. Further mechanistic investigation revealed that Aβ treatment accelerated the autophagy-lysosomal degradation of IR-β and LRP-1 in pBCEC. LRP-1 silencing in pBCEC decreased IR-β levels through post-translational pathways further deteriorating insulin-mediated responses at the BBB. Our findings indicate that LRP-1 proves important for insulin signaling at the BBB. Cerebral Aβ burden in AD may accelerate LRP-1 and IR-β degradation in BCEC thereby contributing to impaired cerebral and cerebromicrovascular insulin effects.
中文翻译：
淀粉样蛋白β通过加速体外和3XTg-AD小鼠血脑屏障内皮细胞中LRP-1和IR-β的自噬溶酶体降解来损害胰岛素信号传导。
异常的胰岛素信号传导构成阿尔茨海默氏病（AD）的早期变化。胰岛素受体（IR）和低密度脂蛋白受体相关蛋白1（LRP-1）在脑毛细血管内皮细胞（BCEC）中表达，形成血脑屏障（BBB）。在那里，胰岛素可能调节LRP-1在从大脑清除Aβ的功能。尚不清楚AD中BBB的IR-β和LRP-1的变化以及胰岛素信号的变化。在本文中，我们确定与NTg小鼠相比，9个月大的雄性和雌性3XTg-AD（PS1M146V，APPSwe和tauP301L）大脑和脑血管IR-β水平降低，这在胰岛素介导的信号应答中很重要。大脑IR-β水平降低对应于大脑中胰岛素信号和LRP-1水平受损。3XTg-AD小鼠脑和脑血管IR-β和LRP-1水平降低与自噬标记物LC3B水平升高相关。在这两种基因型中，高脂饮食（HFD）喂养均降低了脑和肝脏LRP-1的表达，并增加了脑Aβ的负担，而不会影响脑血管LRP-1和IR-β的水平。使用初级猪（p）BCEC进行的体外研究表明，Aβ肽1-40或1-42（240 nM）降低了细胞水平以及LRP-1和IR-β的相互作用，从而干扰了胰岛素介导的信号传导。进一步的机理研究表明，Aβ处理加速了pBCEC中IR-β和LRP-1的自噬溶酶体降解。pBCEC中的LRP-1沉默通过翻译后途径降低了IR-β水平，进一步恶化了BBB胰岛素介导的反应。我们的发现表明LRP-1被证明对BBB的胰岛素信号传导很重要。AD中的大脑Aβ负担可能会加速BCEC中的LRP-1和IR-β降解，从而导致受损的脑和脑微血管胰岛素作用。
更新日期：2019-07-02
中文翻译：
淀粉样蛋白β通过加速体外和3XTg-AD小鼠血脑屏障内皮细胞中LRP-1和IR-β的自噬溶酶体降解来损害胰岛素信号传导。
异常的胰岛素信号传导构成阿尔茨海默氏病（AD）的早期变化。胰岛素受体（IR）和低密度脂蛋白受体相关蛋白1（LRP-1）在脑毛细血管内皮细胞（BCEC）中表达，形成血脑屏障（BBB）。在那里，胰岛素可能调节LRP-1在从大脑清除Aβ的功能。尚不清楚AD中BBB的IR-β和LRP-1的变化以及胰岛素信号的变化。在本文中，我们确定与NTg小鼠相比，9个月大的雄性和雌性3XTg-AD（PS1M146V，APPSwe和tauP301L）大脑和脑血管IR-β水平降低，这在胰岛素介导的信号应答中很重要。大脑IR-β水平降低对应于大脑中胰岛素信号和LRP-1水平受损。3XTg-AD小鼠脑和脑血管IR-β和LRP-1水平降低与自噬标记物LC3B水平升高相关。在这两种基因型中，高脂饮食（HFD）喂养均降低了脑和肝脏LRP-1的表达，并增加了脑Aβ的负担，而不会影响脑血管LRP-1和IR-β的水平。使用初级猪（p）BCEC进行的体外研究表明，Aβ肽1-40或1-42（240 nM）降低了细胞水平以及LRP-1和IR-β的相互作用，从而干扰了胰岛素介导的信号传导。进一步的机理研究表明，Aβ处理加速了pBCEC中IR-β和LRP-1的自噬溶酶体降解。pBCEC中的LRP-1沉默通过翻译后途径降低了IR-β水平，进一步恶化了BBB胰岛素介导的反应。我们的发现表明LRP-1被证明对BBB的胰岛素信号传导很重要。AD中的大脑Aβ负担可能会加速BCEC中的LRP-1和IR-β降解，从而导致受损的脑和脑微血管胰岛素作用。
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