Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies.
Paras S MinhasJeffrey R JonesAmira Latif-HernandezYuki SugiuraAarooran S DurairajQian WangSiddhita D MhatreTakeshi UenakaJoshua CrapserTravis E ConleyHannah E EnnerfeltYoo Jin JungLing LiuPraveena PrasadBrenita C JenkinsYeonglong Albert AyMatthew MatrongoloRyan GoodmanTraci NewmeyerKelly J HeardAustin KangEdward N WilsonTao YangErik M UllianGeidy E SerranoThomas G BeachMarius WernigJoshua D RabinowitzMakoto SuematsuFrank M LongoMelanie R McReynoldsFred H GageKatrin I AndreassonPublished in: Science (New York, N.Y.) (2024)
Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer's disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid β and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor-dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter-dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.
Keyphrases
- cerebral ischemia
- subarachnoid hemorrhage
- mouse model
- temporal lobe epilepsy
- cerebrospinal fluid
- blood brain barrier
- papillary thyroid
- spinal cord
- squamous cell carcinoma
- signaling pathway
- working memory
- mild cognitive impairment
- radiation therapy
- neuropathic pain
- multiple sclerosis
- combination therapy
- mesenchymal stem cells
- young adults
- cell therapy
- locally advanced
- lymph node metastasis
- case control
- smoking cessation