Effect of AmyTrap, an amyloid-β binding drug, on Aβ induced mitochondrial dysfunction and tau phosphorylation in cultured neuroblastoma cells
Effect of AmyTrap, an amyloid-β binding drug, on Aβ induced mitochondrial dysfunction and tau phosphorylation in cultured neuroblastoma cells
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DOI：
10.1007/s11011-019-00520-2
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发表时间：
2020-05-04
影响因子：
3.6
通讯作者：
Sundaram, Pazhani
中科院分区：
文献类型：
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作者：
Gandbhir, Omkar;Sundaram, Pazhani
阿尔茨海默病(AD)是导致痴呆症的最常见原因，全球有2500万人受到影响。淀粉样β蛋白(Aβ)在线粒体中的积累对丙酮酸脱氢酶(PDH)、琥珀酸脱氢酶(SDH)、氧化戊二酸脱氢酶(OGDH)等关键酶产生不利影响。Aβ的积累也被认为增加了Tau的表达和病理。在中毒状态下，tau会导致突触损伤，导致记忆和认知功能障碍。我们正在开发一种治疗AD的药物，即AmyTrap。有效的药理成分是一种逆转录病毒，这是一种与贝塔结合的多肽，可以隔离A贝塔。我们想要研究AmyTrap多肽对Aβ诱导的线粒体功能障碍和Tau磷酸化的影响。因此，我们用野生型Aβ、突变型AβY(10)A、AmyTrap肽(RI-肽)或Aβ+RI-肽处理SH-SY5Y神经母细胞瘤细胞72小时，已知突变型AβY(10)A影响Aβ的自聚集特性，因为这种Tyr(10)是自聚集所必需的。正如预期的那样，AβY(10)A逆转了PDH、OGDH和SDH功能障碍，使其接近正常水平。此外，AβY(10)A成功逆转了Tau的磷酸化，表明Tyr(10)也与Aβ诱导的细胞毒性有关。Ri肽能显著逆转SDH功能障碍，但对PDH和Tau的磷酸化作用有限。这一发现表明，Aβ上的Tyr(10)在自我聚集中起着关键作用。有必要进行进一步的研究，以扩大这些发现。
Alzheimer's Disease (AD) is the most common cause of dementia, affecting 25 million people worldwide. Accumulation of Amyloid-beta (A beta) in the mitochondria has been shown to adversely affect key enzymes including pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), oxoglutarate dehydrogenase (OGDH). Accumulation of A beta is also believed to increase Tau expression and pathology. Tau, in its toxic state, results in synaptic damage causing memory and cognitive dysfunction. We are developing a drug to treat AD namely AmyTrap. The active pharmacological ingredient is a retro inverso, A beta-binding peptide which sequesters A beta. We wanted to examine the effect of AmyTrap peptide on A beta-induced mitochondrial dysfunction and Tau phosphorylation. Therefore, we treated SH-SY5Y neuroblastoma cells with wild-type A beta, a mutant A beta Y(10)A, AmyTrap peptide (RI-peptide), or A beta and RI-peptide for 72 h. The mutant A beta Y(10)A is known to impact the self-aggregating property of A beta as this Tyr(10) is essential for self-aggregation. As expected, A beta Y(10)A reversed PDH, OGDH and SDH dysfunction to near normal levels. Further, A beta Y(10)A successfully reversed Tau phosphorylation, suggesting that Tyr(10) is also associated with A beta-induced cytotoxicity. RI-peptide was able to significantly reverse SDH dysfunction with limited effect on PDH and Tau phosphorylation. The findings are suggestive that the Tyr(10) on A beta plays a critical role in the self-aggregation. Further studies are warranted to expand these findings.