The Institute for Basic Science demonstrates that astrocytic enzyme SIRT2 catalyzes excessive GABA production and contributes to memory impairment in Alzheimer’s. Using molecular and imaging analyses in transgenic mice, the team shows that inhibiting astrocytic SIRT2 attenuates GABA release and restores working memory performance, providing a targeted strategy for modulating neuroinflammation-driven cognitive decline.

Key points

• Identification of SIRT2 and ALDH1A1 as key enzymes driving astrocytic GABA overproduction.
• Selective inhibition of astrocytic SIRT2 reduces GABA release and rescues Y-maze working memory deficits.
• Elevated SIRT2 expression confirmed in both Alzheimer’s mouse model astrocytes and human patient brain tissue.
• Study combines molecular analysis, microscopic imaging, and electrophysiology to elucidate enzyme roles.
• Decoupling GABA synthesis from H₂O₂ generation enables precise targeting of inhibitory signaling.

Why it matters: This study shifts the paradigm from neuron-centric to glia-mediated mechanisms in Alzheimer’s, highlighting SIRT2 as a selective modulator of inhibitory signaling. By decoupling GABA from oxidative stress, it opens paths to precision therapies aimed at astrocyte reactivity, potentially improving cognitive outcomes with fewer off-target effects.