Can we catch the second loach employing BACE1 inhibition, even as the first one might be escaping?
Can we catch the second loach employing BACE1 inhibition, even as the first one might be escaping?
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即使第一个可能逃脱，我们也可以通过使用BACE1抑制来捕获第二个LOACH吗？
DOI：
10.1111/jdi.13640
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发表时间：
2021-11
影响因子：
3.2
通讯作者：
Yokote K
中科院分区：
文献类型：
--
作者：
Ono H;Yokote K
肥胖、糖尿病和阿尔茨海默病（AD）正变得越来越普遍，特别是在老龄化人口中，并且对患者及其家庭的生活质量产生不利影响。这些病症已被证明是相互关联的，并且AD最近被称为3型糖尿病，因为神经元胰岛素抵抗是AD的病理生理学的基础。基于淀粉样蛋白β假说，B位点淀粉样蛋白前体蛋白裂解酶1（BACE 1）是AD最有希望的药物靶点。BACE 1是一种β-分泌酶，其加工淀粉样蛋白前体蛋白以产生淀粉样蛋白B-42（Ab 42）。最近，在连续的出版物中，Meakin等人1，2报道了小鼠中BACE 1的抑制不仅抑制了Ab 42的形成，而且还预防了肥胖、胰岛素抵抗和血管功能障碍3。饮食诱导的肥胖（DIO）小鼠在血流中以及在它们的血管壁中具有更高的Ab 42水平。全身缺失BACE 1，以及其抑制剂的特定，逆转血管功能障碍与恢复一氧化氮（NO）的生产，这也是受损的DIO。抑制BACE 1通过蛋白激酶B磷酸化增强内皮NO合酶活化相比之下，在病理生理水平输注人Ab 42使正常小鼠中的内皮功能障碍恶化。作者还表明，血液Ab 42水平与血管功能障碍相关，即使在人类中也是如此。他们得出结论，BACE 1抑制是一种有希望的治疗血管疾病的方法，血管疾病是肥胖和糖尿病的危及生命的并发症3。虽然他们的发现强烈表明Ab 42是DIO诱导的血管功能障碍的原因，但由于长期治疗引起的体重变化似乎可能是一个混杂因素（图1）。以前，相同的作者提出了明确的证据表明，BACE 1抑制保护免受DIO 1，2。一致地，DIO小鼠的体重通过Ab 42输注显著增加，并且通过BACE 1抑制剂治疗显著降低3。由于Ab 42输注4周显著增加体重，Ab 42本身诱导的肥胖可能是血管功能障碍的部分原因。同样，BACE 1抑制剂引起的体重下降可能会减轻DIO小鼠的血管功能障碍。此外，所有实验均在相对慢性阶段（> 4周）进行。确定急性输注Ab 42或BACE 1抑制剂是否产生类似的作用将是有趣的，因为NO产生和内皮NO合酶、蛋白激酶B和腺苷一磷酸活化的蛋白激酶的磷酸化可能响应于这些干预而快速发生。旨在检测血管功能障碍早期变化的实验，以及避免体重差异影响的配对喂养，可能会在未来的研究中阐明这些观点。
Obesity, diabetes and Alzheimer’s disease (AD) are becoming increasingly common, especially in the aging population, and are adversely affecting the quality of life of patients and their families. These conditions have been shown to be interrelated, and AD has recently been referred to as type 3 diabetes, because neuronal insulin resistance underlies the pathophysiology of AD. Based on the amyloid-beta hypothesis, b-site amyloid precursor proteincleaving enzyme 1 (BACE1) is the most promising drug target for AD. BACE1 is a b-secretase that processes the amyloid precursor protein to generate amyloid b-42 (Ab42). Recently, in consecutive publications, Meakin et al. 1, 2 reported that the suppression of BACE1 in mice not only suppressed Ab42 formation, but also prevented obesity, insulin resistance and vascular dysfunction3. Diet-induced obese (DIO) mice have higher Ab42 levels in the bloodstream, as well as in their vessel walls. Systemic deletion of BACE1, as well as its inhibition by a specific inhibitor, reversed vascular dysfunction with recovery of nitric oxide (NO) production, which is also impaired in DIO. Inhibition of BACE1 enhances endothelial NO synthase activation by protein kinase B phosphorylation. In contrast, infusion of human Ab42 at the pathophysiological level worsened endothelial dysfunction in normal mice. The authors also showed that blood Ab42 levels correlate with vascular dysfunction, even in humans. They concluded that BACE1 inhibition is a promising treatment for vascular diseases, which are life-threatening complications of obesity and diabetes3.While their findings strongly suggest that Ab42 is the cause of DIO-induced vascular dysfunction, it appears that bodyweight changes due to chronic treatment could be a confounder (Figure 1). Previously, the same authors presented clear evidence that BACE1 inhibition protects against DIO1, 2. Consistently, the bodyweights of DIO mice were significantly increased by Ab42 infusion and significantly decreased by BACE1 inhibitor treatment3. As 4 weeks of Ab42 infusion significantly increased bodyweight, obesity induced by Ab42 itself might be a partial cause of vascular dysfunction. Likewise, the decrease in bodyweight caused by the BACE1 inhibitor might reduce vascular dysfunction in DIO mice. Furthermore, all experiments were carried out at a relatively chronic stage (> 4 weeks). It would be interesting to ascertain whether acute infusion of Ab42 or BACE1 inhibition produces similar effects, because NO production and phosphorylation of endothelial NO synthase, protein kinase B and adenosine monophosphate-activated protein kinase might occur rapidly in response to such interventions. Experiments designed to detect earlier changes in vascular dysfunction, and pair-feeding to avoid effects attributable to bodyweight differences, might clarify these points in future studies.
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DOI：
10.1042/bj20110512
发表时间：
2012-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Meakin PJ;Harper AJ;Hamilton DL;Gallagher J;McNeilly AD;Burgess LA;Vaanholt LM;Bannon KA;Latcham J;Hussain I;Speakman JR;Howlett DR;Ashford ML
通讯作者：
Ashford ML
影响因子：
8.2
作者：
Plucińska K;Dekeryte R;Koss D;Shearer K;Mody N;Whitfield PD;Doherty MK;Mingarelli M;Welch A;Riedel G;Delibegovic M;Platt B
通讯作者：
Platt B
DOI：
10.1136/bmj.n156
发表时间：
2021-02-25
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Ackley SF;Zimmerman SC;Brenowitz WD;Tchetgen Tchetgen EJ;Gold AL;Manly JJ;Mayeda ER;Filshtein TJ;Power MC;Elahi FM;Brickman AM;Glymour MM
通讯作者：
Glymour MM
影响因子：
4.6
作者：
Meakin PJ;Jalicy SM;Montagut G;Allsop DJP;Cavellini DL;Irvine SW;McGinley C;Liddell MK;McNeilly AD;Parmionova K;Liu YR;Bailey CLS;Dale JK;Heisler LK;McCrimmon RJ;Ashford MLJ
通讯作者：
Ashford MLJ
影响因子：
15.9
作者：
Meakin, Paul J.;Coull, Bethany M.;Ashford, Michael L. J.
通讯作者：
Ashford, Michael L. J.