Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 114, 16th Street, Charlestown, MA 02129, USA.
Cells. 2024 Sep 24;13(19):1600. doi: 10.3390/cells13191600.
Glutamate transporter-1 (GLT-1) dynamics are implicated in excitotoxicity and Alzheimer's disease (AD) progression. Early stages of AD are often marked by hyperactivity and increased epileptiform activity preceding cognitive decline. Previously, we identified a direct interaction between GLT-1 and Presenilin 1 (PS1) in the brain, highlighting GLT-1 as a promising target in AD research. This study reports the significance of this interaction and uncovers a novel role of GLT-1 in modulating amyloid-beta (Aβ) production. Overexpression of GLT-1 in cells reduces the levels of Aβ40 and Aβ42 by decreasing γ-secretase activity pertinent to APP processing and induces a more "open" PS1 conformation, resulting in decreased Aβ42/40 ratio. Inhibition of the GLT-1/PS1 interaction using cell-permeable peptides produced an opposing effect on Aβ, highlighting the pivotal role of this interaction in regulating Aβ levels. These findings emphasize the potential of targeting the GLT-1/PS1 interaction as a novel therapeutic strategy for AD.
谷氨酸转运体-1（GLT-1）的动态变化与兴奋性毒性和阿尔茨海默病（AD）的进展有关。AD 的早期阶段常以认知能力下降之前的过度活跃和癫痫样活动增加为特征。此前，我们在大脑中发现了 GLT-1 与早老素 1（PS1）之间的直接相互作用，这突显了 GLT-1 作为 AD 研究中一个有前途的靶点。本研究报告了这种相互作用的重要性，并揭示了 GLT-1 在调节淀粉样蛋白-β（Aβ）产生中的新作用。细胞中 GLT-1 的过表达通过降低与 APP 加工相关的 γ-分泌酶活性来降低 Aβ40 和 Aβ42 的水平，并诱导 PS1 构象更为“开放”，从而降低 Aβ42/40 比值。使用细胞通透性肽抑制 GLT-1/PS1 相互作用对 Aβ 产生了相反的影响，突出了这种相互作用在调节 Aβ 水平方面的关键作用。这些发现强调了靶向 GLT-1/PS1 相互作用作为 AD 新型治疗策略的潜力。
