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.

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 GLT-1/PS1 interaction as a novel therapeutic strategy for AD.