There is increasing evidence linking the kynurenine pathway (KP) to Alzheimer’s disease (AD) pathology, though the precise mechanisms remain elusive. Elevated KP activity in AD is associated with hallmark pathologies such as amyloid-β plaques and tau tangles. The prevailing hypothesis suggests that KP activation produces neurotoxic metabolites like quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK), which contribute to excitotoxicity and neurodegeneration (see June 2022 highlight). A recent systematic review and meta-analysis by Maes et al. (2022) found evidence of AD patients exhibiting tryptophan (TRP) depletion and an elevated kynurenine (KYN)/TRP ratio. However, the clinical relevance of targeting IDO1 in AD pathophysiology remain to be elucidated.
Building on this, Dr. Minhaus et al. propose a novel mechanism where IDO1 disrupts glucose metabolism in astrocytes, particularly under the influence of amyloid-β and tau. Data from their in vitro study demonstrate that amyloid-β and tau peptides upregulate IDO1 expression, increasing KYN levels and activating AhR signaling, which suppresses glucose metabolism in astrocytes but not neurons. Importantly, they demonstrated that IDO inhibition, either pharmacologically or genetically, restores astrocytic bioenergetics in the presence of these pathogenic peptides.
To demonstrate the functional aspects of the in vitro findings, they used both amyloid and tau in vivo models of AD, showing that IDO1 activation was associated with amyloid-β and tau accumulation. Inhibiting IDO1 led to the restoration of suppressed HIF1α-dependent glycolytic metabolism in astrocytes, thereby increasing lactate levels, which are crucial to support neuronal mitochondrial respiration and synaptic activity. In other words, IDO1 inhibition enabled astrocytic lactate production to support neuronal metabolism for long-term memory and improved hippocampal memory deficits caused by AD pathogenic peptides. Interestingly, astrocyte reactivity (reflected by the GFAP marker) was not modulated by IDO1 inhibition.
Dr. Minhaus et al. introduced a novel mechanism implicating the KP in CNS pathophysiology, where AhR-dependent IDO1 activation disrupts energy metabolism. This mechanism may potentially extend beyond AD, offering insights into other CNS disorders where IDO1 upregulation plays a role. Interestingly, the correlation between KP and cognitive function appears to vary depending on glucose metabolism status (see work by Dr Lieke Bakker et al.), highlighting the intricate relationship between KP, metabolic state, and CNS function. Importantly, Minhaus’ study unveils a critical mechanism where IDO1-AhR signaling influences pathology not through classical AhR downstream targets and immunoregulation, but by competing for the AhR nuclear translocator (ARNT), thereby limiting HIF1α’s regulation of glycolytic gene expression. This mechanism underscores the broader implications of KP-induced energy homeostasis disruption in neurodegenerative diseases.