BBB Seminar: Katrin Andreasson

Katrin Andreasson (external link), Stanford University School of Medicine, USA

Cerebral glucose hypometabolism is a defining feature of aging and neurodegenerative disease, but the upstream mechanisms responsible for this decline are not completely understood. We identified astrocytic indoleamine 2,3-dioxygenase 1 (IDO1) as a metabolic checkpoint activated by amyloid-β and tau. IDO1-dependent kynurenine production suppresses astrocyte glycolysis and lactate generation, disrupting metabolic support of neurons. Inhibition of IDO1 restores hippocampal glucose metabolism, astrocyte-to-neuron lactate transfer, synaptic plasticity, and cognition across mouse models of amyloid and tau pathology. This metabolic rescue is conserved in human Alzheimer’s disease astrocyte–neuron cultures, identifying astrocyte metabolism as a reversible pathway downstream of distinct neuropathologies.

More recent studies extend this framework to the aging peripheral immune compartment. In tissue-resident macrophages, age-dependent prostaglandin E2 signaling through the EP2 receptor impairs mitochondrial function and the clearance of senescent neutrophils. Genetic deletion or pharmacologic inhibition of EP2 restores macrophage homeostatic function, reduces inflammatory tissue injury, and limits cognitive and multi-organ decline. Ongoing work further identifies the cerebrovascular interface as a transducer of EP2-mediated systemic immune aging to the brain. Signals from the aged peripheral immune compartment promote brain endothelial senescence and barrier dysfunction, interferon-responsive and metabolically impaired astrocyte states, and uncoupling of neuronal activity from lactate availability. Together, these studies define central immune–metabolic and peripheral immune–vascular–astrocytic pathways that regulate cerebral metabolism and suggest that restoring immune homeostasis could enhance brain resilience in aging and neurodegenerative disease.

Chairperson: Mathias Ziegler, Department of Biomedicine