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 blockade also rescues hippocampal long-term potentiation in
a monocarboxylate transporter (MCT)-dependent manner, suggesting that IDO1
activity disrupts astrocytic metabolic support of neurons. Indeed, in
vitro mass-labeling of human astrocytes demonstrates that IDO1 regulates
astrocyte generation of lactate that is then taken up by human
neurons.  In co-cultures of astrocytes and neurons derived from
AD subjects, deficient astrocyte lactate production and transfer to
neurons was corrected by IDO1 inhibition, resulting in improved neuronal
glucose metabolism.  Thus, IDO1 activity disrupts astrocytic
metabolic support of neurons across both amyloid and tau pathologies and
in a model of AD iPSC-derived neurons. These findings also suggest that
IDO1 inhibitors developed for adjunctive therapy in cancer could be
repurposed for treatment of amyloid- and tau-mediated neurodegenerative
diseases.