Oral GLP-1 receptor agonist promotes astrocyte-neuron lactate and lipid transfer with neuroprotective effects.

Glucagon-like peptide-1 receptor (GLP-1R) activation is widely assumed to regulate the metabolic disorder in Alzheimer's disease (AD). However, direct evidence for this hypothesis is lacking, and currently, there is no oral GLP-1R agonist with effective blood-brain barrier-penetrating ability. Here, we show that a candidate peptide, OHP2, an oral GLP-1R agonist with blood-brain barrier permeability, exhibits promising therapeutic potential for AD. OHP2 primarily activates GLP-1R on astrocytes, leading to increased aerobic glycolysis and driving lactate release. Astrocyte-derived lactate is taken up by neurons and elevates histone H3 lysine 9 lactylation (H3K9la), which in turn facilitates lipid transport from neurons back to astrocytes. This astrocyte-neuron metabolic coupling sustains continuous aerobic glycolysis and offers a potential treatment strategy for AD. The H3K9la derived from OHP2 links glucose and lipid metabolic cycle and facilitates metabolic coupling between astrocytes and neurons, which leads to remission of metabolic disturbances in AD. Thus, our study provides a new candidate molecule for drug research in treating AD and illustrates that intracerebral GLP-1R activation, which facilitates astrocyte-neuron metabolic coupling, may be a potential approach for the treatment of AD.