Restoring hippocampal glucose metabolism rescues cognition across Alzheimer disease pathologies

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer Disease (AD) and recent proteomic studies highlight a disruption of glial carbohydrate metabolism with disease progression.  Here, we report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN) in the first step of the kynurenine pathway, rescues hippocampal memory function and plasticity in preclinical models of amyloid and tau pathology by restoring astrocytic metabolic support of neurons.  Activation of IDO1 in astrocytes by amyloid-beta and tau oligomers, two major pathologic effectors in AD, increases KYN and suppresses glycolysis in an AhR-dependent manner. Conversely, pharmacological IDO1 inhibition restores glycolysis and lactate production. In amyloid-producing APPSwe-PS1∆E9 and 5XFAD mice and in tau-producing P301S mice, IDO1 inhibition restores spatial memory and improves hippocampal glucose metabolism by metabolomic and MALDI-MS analyses. IDO1 blocka..., Metabolites were extracted from isolated astrocytes and neurons in a -80˚C 80:20 methanol:water solution in a volume of 1.5 ml per 1x106 cells, vortexed, incubated on dry ice for 10 min, and centrifuged at 16,000 g for 20 min, and the supernatant was assayed by LC-MS analysis. Extracts were analyzed within 24 hr by liquid chromatography coupled to a mass spectrometer (LC-MS). The LC-MS method involved hydrophilic interaction chromatography (HILIC) coupled to the Q Exactive PLUS mass spectrometer (Thermo Scientific) 7 (17). The LC separation was performed on an XBridge BEH Amide column (150 mm 3 2.1 mm, 2.5 mm particle size, Waters, Milford, MA). Solvent A was 95%: 5% H2O: acetonitrile with 20 mM ammonium bicarbonate, and solvent B was acetonitrile. The gradient was 0 min, 85% B; 2 min, 85% B; 3 min, 80% B; 5 min, 80% B; 6 min, 75% B; 7 min, 75% B; 8 min, 70% B; 9 min, 70% B; 10 min, 50% B; 12 min, 50% B; 13 min, 25% B; 16 min, 25% B; 18 min, 0% B; 23 min, 0% B; 24 min, 85% B; and 30 min..., , # Restoring hippocampal glucose metabolism rescues cognition across Alzheimer disease pathologies

Access this dataset on Dryad](DOI: 10.5061/dryad.dbrv15f9j)

The excel files located in this dryad dataset contain normalized values (z-score) of multi-analyte cytokine array (Luminex), qRT-PCR of selected genes, as well as metabolomics from several different experiments. Experiments are from both in vitro and in vivo astrocytes as well as hippocampus tissue. Experimental conditions are listed below. 

## Description of Data and file structure

Source Data 1H.xlsx

qRT-PCR of AhR-signaling genes in vitro post-natal Mouse Astrocytes treated with Vehicle (Veh), oTau+oAB (oligomeric Tau + oligomeric Amyloid beta), Ido1 inhibitor PF068. First column contains Gene names; subsequent columns contain control and experimental groups. 

Source Data 1I.xlsx

Hif-1a signaling qRT-PCR in vitro post-natal Mouse Astrocytes treated with Vehicle (Veh), oTau+oAB (oligomeric Tau + oligomeric Amyloid beta), I...