Ethyl Acetate Fraction of Zanthoxylum bungeanum Ameliorates Cognitive Deficit by Facilitating the PHGDH-Dependent Astrocyte-Neuron Serine Shuttle in Aging Mice

Enhancing the astrocyte-neuron serine shuttle to maintain N-methyl-d-aspartate receptor (NMDARs)-mediated neuronal synaptic plasticity is an effective strategy to alleviate age-related cognitive deficit (ARCD). This study investigated the mechanisms by which the ethyl acetate extract of Zanthoxylum bungeanum Maxim. (EA), a famous spiceberry, attenuates ARCD by established aging mice and the coculture system of U87 and SH-SY5Y cells model using d-galactose stimulation. Results display that EA significantly elevated the astrocyte-neuron serine shuttle and activated the NMDARs/calmodulin-dependent kinase II (CaMKII) pathway. Moreover, EA markedly enhanced glycolytic flux in the brain of aging mice and U87 cells, evidenced by the elevated enzymatic activities of hexokinase (HK), 6-phosphofructokinase (PFK), and pyruvate kinase (PK), increased adenosine triphosphate (ATP), lactate-to-pyruvate ratio, pyruvate contents, and lactate release. Furthermore, EA significantly alleviated synaptic morphology and elevated synuclein (SYN), postsynaptic density protein 95 (PSD95), and microtubule-associated protein-2 (MAP2) protein levels. Interestingly, NCT503, a phosphoglycerate dehydrogenase (PHGDH) inhibitor, reversed these effects of EA. Finally, EA markedly reduced neuropathological impairment and cognitive impairment in aging mice. The study confirmed that EA promoted astrocytic PHGDH-mediated l-serine production and the astrocyte-neuron serine shuttle to activate the NMDARs/CaMKII pathway in neurons to relieve ARCD.