Alteration of brain aerobic glycolysis is often observed early in the course of Alzheimer's disease (AD). Whether and how such metabolic dysregulation contributes to both synaptic plasticity and behavioral deficits in AD is not known. Here, we show that the astrocytic L-serine biosynthesis pathway, which branches from glycolysis, is impaired in young AD mice and in AD patients. L-serine is the precursor of D-serine, a co-agonist of synaptic NMDA receptors (NMDARs) required for synaptic plasticity. Accordingly, AD mice display a lower occupancy of the NMDAR co-agonist site as well as synaptic and behavioral deficits. Similar deficits are observed following inactivation of the L-serine synthetic pathway in hippocampal astrocytes, supporting the key role of astrocytic L-serine. Supplementation with L-serine in the diet prevents both synaptic and behavioral deficits in 3xTg-AD mice. Our findings reveal that astrocytic glycolysis controls cognitive functions and suggest oral L-serine as a ready-to-use therapy for AD.

The striatum, a major component of the brain basal nuclei, is central for planning and executing voluntary movements and undergoes lesions in neurodegenerative disorders such as Huntington disease. To perform highly integrated tasks, the striatum relies on a complex network of communication within and between brain regions with a key role devoted to secreted molecules. To characterize the rat striatum secretome, we combined in vivo microdialysis together with proteomics analysis of trypsin digests and peptidomics studies of native fragments. This versatile approach, carried out using different microdialysis probes and mass spectrometer devices, allowed evidencing with high confidence the expression of 88 proteins and 100 processed peptides. Their secretory pathways were predicted by in silico analysis. Whereas high molecular weight proteins were mainly secreted by the classical mode (94%), low molecular weight proteins equally used classical and non-classical modes (53 and 47%, respectively). In addition, our results suggested alternative secretion mechanisms not predicted by bioinformatics tools. Based on spectrum counting, we performed a relative quantification of secreted proteins and peptides in both basal and neuronal depolarization conditions. This allowed detecting a series of neuropeptide precursors and a 6-fold increase for neurosecretory protein VGF and In mammalian brain, the striatum plays a critical role for planning and executing voluntary movements and is also involved in cognitive processes (1). The striatum makes use of a complex network architecture connecting specialized anatomical structures to achieve these highly integrated tasks. It receives projections from primary sensory and motor cortices as well as motor thalamic nuclei and sends projections to downstream basal ganglia structures, thereby influencing the control of cortical and brainstem motor systems (2). In this context, communication within and between brain structures appears as a key element for brain functioning. For cell-to-cell communication, secreted proteins play a pivotal regulatory role. To enter the secretory pathway, it has been long assumed that an N-terminal signal peptide sequence is strictly required. However, recent studies have shown that endoplasmic reticulum-and Golgi-independent or non-classical mechanisms may be responsible for protein secretion (3). The extracellular medium is thus more complex than previously suspected, and its characterization has gained a special interest (4, 5). In silico analyses suggest that mature proteins secreted via classical and non-classical mechanisms share common physicochemical properties (6). In this respect, proteomics is a powerful approach for systematically analyzing proteins present in the extracellular medium (7-9). For neurochemical monitoring of the secretome within the brain, only a few tools provide an appropriate insight into its spatial and temporal dynamics. Microdialysis, in particular, has been shown to be a powerful tool for exploring the extracellular content o...