Hategan Alina, Bianchet Mario A, Steiner Joseph, Karnaukhova Elena, Masliah Eliezer, Fields Adam, Lee Myoung-Hwa, Dickens Alex M, Haughey Norman, Dimitriadis Emilios K, Nath Avindra
Section of Infections of the Nervous System, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Nat Struct Mol Biol. 2017 Apr;24(4):379-386. doi: 10.1038/nsmb.3379. Epub 2017 Feb 20.
Deposition of amyloid-β plaques is increased in the brains of HIV-infected individuals, and the HIV transactivator of transcription (Tat) protein affects amyloidogenesis through several indirect mechanisms. Here, we investigated direct interactions between Tat and amyloid-β peptide. Our in vitro studies showed that in the presence of Tat, uniform amyloid fibrils become double twisted fibrils and further form populations of thick unstructured filaments and aggregates. Specifically, Tat binding to the exterior surfaces of the Aβ fibrils increases β-sheet formation and lateral aggregation into thick multifibrillar structures, thus producing fibers with increased rigidity and mechanical resistance. Furthermore, Tat and Aβ aggregates in complex synergistically induced neurotoxicity both in vitro and in animal models. Increased rigidity and mechanical resistance of the amyloid-β-Tat complexes coupled with stronger adhesion due to the presence of Tat in the fibrils may account for increased damage, potentially through pore formation in membranes.
在HIV感染者的大脑中，β淀粉样蛋白斑的沉积会增加，并且HIV转录反式激活因子（Tat）蛋白通过多种间接机制影响淀粉样蛋白生成。在此，我们研究了Tat与β淀粉样蛋白肽之间的直接相互作用。我们的体外研究表明，在存在Tat的情况下，均匀的淀粉样纤维会变成双螺旋纤维，并进一步形成大量粗大的无结构细丝和聚集体。具体而言，Tat与Aβ纤维的外表面结合会增加β折叠的形成以及横向聚集形成粗大的多纤维结构，从而产生具有更高刚性和机械抗性的纤维。此外，Tat与Aβ聚集体形成的复合物在体外和动物模型中均协同诱导神经毒性。淀粉样β-Tat复合物更高的刚性和机械抗性，加上由于纤维中存在Tat而具有更强的粘附力，可能是造成损伤增加的原因，这可能是通过在膜中形成孔来实现的。
