Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA.
Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Stem Cell Reports. 2023 Dec 12;18(12):2434-2450. doi: 10.1016/j.stemcr.2023.10.011. Epub 2023 Nov 9.
The SORL1 gene (SORLA) is strongly associated with risk of developing Alzheimer's disease (AD). SORLA is a regulator of endosomal trafficking in neurons and interacts with retromer, a complex that is a "master conductor" of endosomal trafficking. Small molecules can increase retromer expression in vitro, enhancing its function. We treated hiPSC-derived cortical neurons that are either fully deficient, haploinsufficient, or that harbor one copy of SORL1 variants linked to AD with TPT-260, a retromer-enhancing molecule. We show significant increases in retromer subunit VPS26B expression. We tested whether endosomal, amyloid, and TAU pathologies were corrected. We observed that the degree of rescue by TPT-260 treatment depended on the number of copies of functional SORL1 and which SORL1 variant was expressed. Using a disease-relevant preclinical model, our work illuminates how the SORL1-retromer pathway can be therapeutically harnessed.
SORL1 基因（SORLA）与阿尔茨海默病（AD）的发病风险密切相关。SORLA 是神经元内体运输的调节剂，与 retromer 相互作用，后者是内体运输的“主导体”。小分子可以在体外增加 retromer 的表达，从而增强其功能。我们用 TPT-260 处理完全缺乏、单倍不足或携带与 AD 相关的 SORL1 变体的 hiPSC 衍生皮质神经元，TPT-260 是一种增强 retromer 的分子。我们发现 retromer 亚基 VPS26B 的表达显著增加。我们测试了内体、淀粉样蛋白和 TAU 病理学是否得到纠正。我们观察到 TPT-260 处理的挽救程度取决于功能性 SORL1 的拷贝数和表达的 SORL1 变体。使用与疾病相关的临床前模型，我们的工作阐明了如何可以治疗性利用 SORL1-retromer 途径。
