"Glutaminolysis Fuels Reactive Astrocytes, Exacerbating Amyloid Pathology in Alzheimer's Disease"

Abstract

Amyloid-β (Aβ) plaques with progressively increasing reactive astrocytes characterize Alzheimer's disease (AD). Reactive astrocytes are regulated by cellular and molecular mechanisms that are known to progress Aβ pathology. However, the metabolic adaptation and metabolites required to fuel these molecular changes in reactive astrocytes remain unknown. Using human AD samples, in vivo amyloid mouse models, and in vitro approaches, we demonstrate that reactive astrocytes utilize glutamine to fuel anaplerosis and meet their metabolic demands, thereby progressing amyloidosis. We show that reactive astrocytes increase Na ⁺ -coupled neutral amino acid transporters for glutamine uptake that are interdependent on Na ⁺ /K ⁺ ATPase. Furthermore, increasing brain-glutamine levels with a high-glutamine diet exacerbated reactive astrocytes, increasing Aβ burden in an amyloid mouse model. We demonstrate that glutamine undergoes glutaminolysis via glutaminase-2/glutamate dehydrogenase-1 enzymes to be incorporated into TCA metabolites for anaplerosis. Pharmacologically or genetically blocking glutaminolysis reduces reactive astrocytes and decreases Aβ pathology in an amyloid mouse. Our findings reveal the first glutamine-dependent metabolic adaptation of reactive astrocytes affecting Aβ pathology, which may be harnessed for AD therapeutic strategies.