Curtis Mary Elizabeth, Smith Tiffany, Blass Benjamin E, Praticò Domenico
Alzheimer's Center at Temple Lewis Katz School of Medicine Temple University Philadelphia Pennsylvania USA.
School of Pharmacy Temple University Philadelphia Pennsylvania USA.
Alzheimers Dement (N Y). 2022 Jul 26;8(1):e12334. doi: 10.1002/trc2.12334. eCollection 2022.
Retromer complex proteins are decreased in Down syndrome (DS) brains and correlate inversely with brain amyloidosis. However, whether retromer dysfunction contributes to the amyloid beta (Aβ) and tau neuropathology of DS remains unknown.
Human trisomic induced Pluripotent Stem Cells (iPSCs) and isogenic controls were differentiated into forebrain neurons, and changes in retromer proteins, tau phosphorylated epitopes, and Aβ levels were assessed in euploid and trisomic neurons using western blot and enzyme-linked immunosorbent assay (ELISA). Genetic overexpression and pharmacological retromer stabilization were used to determine the functional role of the retromer complex system in modulating amyloid and tau pathology.
Trisomic neurons developed age-dependent retromer core protein deficiency associated with accumulation of Aβ peptides and phosphorylated tau isoforms. Enhancing retromer function through overexpression or pharmacological retromer stabilization reduced amyloid and tau pathology in trisomic neurons. However, the effect was greater using a pharmacological approach, suggesting that targeting the complex stability may be more effective in addressing this neuropathology in DS.
Our results demonstrate that the retromer complex is directly involved in the development of the neuropathologic phenotype in DS, and that pharmacological stabilization of the complex should be considered as a novel therapeutic tool in people with DS.
后转运复合物蛋白在唐氏综合征（DS）患者大脑中减少，且与脑淀粉样变性呈负相关。然而，后转运复合物功能障碍是否导致DS的β淀粉样蛋白（Aβ）和tau神经病理学改变仍不清楚。
将人三体诱导多能干细胞（iPSC）及其同基因对照分化为前脑神经元，使用蛋白质免疫印迹法和酶联免疫吸附测定（ELISA）评估整倍体和三体神经元中后转运复合物蛋白、tau磷酸化表位和Aβ水平的变化。采用基因过表达和药物稳定后转运复合物的方法，以确定后转运复合物系统在调节淀粉样蛋白和tau病理学中的功能作用。
三体神经元出现与Aβ肽和磷酸化tau异构体积累相关的年龄依赖性后转运复合物核心蛋白缺乏。通过过表达或药物稳定后转运复合物来增强其功能，可减少三体神经元中的淀粉样蛋白和tau病理学改变。然而，药物方法的效果更佳，这表明针对复合物稳定性可能是解决DS这种神经病理学问题更有效的方法。
我们的结果表明，后转运复合物直接参与DS神经病理表型的发展，并且复合物的药物稳定化应被视为DS患者的一种新型治疗工具。
