Glycine transporter 1 (GlyT1) is a novel therapeutic target for Alzheimer's disease.

Background: Glycine transporter 1 (GlyT1), expressed predominantly in astrocytes, is responsible for the glycine reuptake from the synaptic cleft in the central nervous system. Since glycine exerts dual effects on inhibitory neurotransmission and excitatory neuromodulation as a co‐activator of NMDA receptor, rapid clearance of glycine in a submicromolar range through GlyT1 is important to terminate neuronal signaling. Also, as glycine uptake by GlyT1 is coupled to 2 Na+ and 1 Cl−, the accumulation of glycine in the brain could be toxic due to dysregulation of glycine‐induced metabotropic signaling pathways. Previous reports show that glycine concentration is elevated in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). It could alter glial function which is important for neuroprotection through Aβ phagocytosis. Method: We performed immunohistochemistry with human AD brain to evaluate the GlyT1 expression in the astrocytes. Then, we used an adeno‐associated viral vector (AAV) to overexpress GlyT1 in the brains of AD model mice and conducted water‐maze and Y‐maze to test the cognitive function. Result: We found that GlyT1 is downregulated in the human AD brain, especially in the astrocytes adjacent to the Aβ plaques. Overexpression of GlyT1 in the brain by AAV‐GlyT1 injcetion alleviates the cognitive impairment of AD model mice. Also, phagocytic activity of the astrocytes and microglia in GlyT1‐overexpressed mice brains is increased, suggesting GlyT1‐mediated glycine uptake restores the glial function. Consistently, in vitro experiments show that a high concentration of glycine reduces Aβ phagocytosis of human astrocyte and microglia cell lines, and GlyT1 overexpression rescues the glial function. Also, glycine induces internalization of GlyRs resulting in intracellular Ca2+ accumulation. Conclusion: Our results demonstrate the important role of GlyT1 in glial function in the brain and propose GlyT1 as a novel therapeutic target for Alzheimer's disease. [ABSTRACT FROM AUTHOR]