In amyloid-β and tau-driven Alzheimer's models, astrocyte IDO1 activation impairs glycolysis and lactate production via kynurenine–AhR signaling, starving hippocampal neurons and disrupting synaptic plasticity. Pharmacologic (PF‑06840003) or genetic IDO1 inhibition in mouse and human iPSC-based systems restored astrocytic metabolism, rescued hippocampal glucose uptake, reinstated LTP, and recovered memory performance, despite unchanged amyloid/tau burden.

Background & Mechanism

• Patients and mouse models of Alzheimer's disease (both amyloid-β and tau pathologies) exhibit astrocyte-mediated suppression of glucose metabolism, leading to reduced lactate support for neurons and impaired synaptic function
• Alzheimer's disease features marked glial metabolic impairment, particularly in astrocytes 
• Aβ and tau oligomers upregulate astrocytic IDO1, increasing kynurenine (KYN) and activating the aryl hydrocarbon receptor (AhR).
• AhR signaling suppresses HIF‑1α–dependent glycolytic gene expression, resulting in decreased astrocytic glycolysis, lactate production, and thus impaired neuronal energy support
• IDO1–Kynurenine–AhR axis as the culprit
  • Aβ and tau oligomers upregulate indoleamine-2,3-dioxygenase 1 (IDO1) in astrocytes
  • IDO1 increases conversion of tryptophan → kynurenine (KYN), which activates the aryl hydrocarbon receptor (AhR)
  • AhR signaling competes with HIF‑1α, downregulating glycolytic gene expression, reducing lactate output and metabolite production 

IDO1 Inhibitor Mechanistic Pathway

• Aβ/tau → increased astrocytic IDO1 → elevated KYN → AhR activation.
• AhR impairs HIF‑1α–dependent transcription → reduced glycolysis and lactate flux.
• Neuronal energy starvation → synaptic dysfunction → cognitive deficits.

Experimental Evidence

• Mouse AD models (APP/PS1, 5XFAD, P301S): administration of PF‑06840003 restored astrocyte lactate production, hippocampal glucose metabolism (via metabolomics/MALDI-MS), LTP (via monocarboxylate transporters), and cognitive behavior (Barnes maze, novel object recognition) 
• Human iPSC-derived co-cultures: IDO1 inhibition improved astrocyte lactate output and neuronal glucose uptake 
• IDO1 inhibition restores metabolism and cognition
  • Using pharmacologic inhibition (e.g., PF‑06840003) or genetic deletion of IDO1 in APP/PS1, 5XFAD, and P301S mouse models:
  • Restored glycolysis and lactate production in astrocytes.
  • Improved hippocampal glucose uptake and metabolism (via metabolomics, MALDI-MS).
  • Rescued hippocampal long-term potentiation (LTP) through monocarboxylate transporter–dependent lactate shuttle.
  • Normalized performance in spatial and recognition memory tasks (Barnes maze, novel object recognition)
• Human iPSC and postmortem validation
  • Hippocampal KYN concentrations correlated with Braak stage, linking IDO1–KYN pathway to human pathology
  • In co-cultures from late-onset AD brain donors, IDO1 inhibition reinstated astrocytic lactate production and enhanced neuronal energy metabolism.
  • Postmortem hippocampal tissues showed higher KYN levels correlated with AD Braak stage

Therapeutic Implications

• First demonstration that modulating astrocyte metabolism can restore synaptic and cognitive function across classic AD models.
• IDO1 inhibitors (e.g., PF‑06840003), currently in oncology trials, could be repurposed for AD to improve metabolic resilience without altering amyloid or tau loads 

IDO1 Inhibitor Investigational / Prescription Agents

• PF‑06840003: CNS-penetrant IDO1 inhibitor that restored astrocytic glycolysis, hippocampal synaptic function, and behavior in diverse AD mouse models .
• Others in clinical development for oncology include epacadostat, linrodostat, and navoximod.

IDO1 Inhibitor Over-the-Counter (OTC) / Natural Compounds

Although no OTC drugs specifically inhibit IDO1 at pharmacologically relevant doses, several natural compounds demonstrate measurable IDO1 activity in vitro:

However, none have been tested in humans for CNS or AD indications; potency, specificity, and bioavailability remain uncertain.

Clinical Relevance for Neurologists

• Biomarker opportunity:
  • Kynurenine levels may reflect disease stage or response to IDO1-targeted treatment.
  • Kynurenine/tryptophan ratios, lactate shuttle integrity, and glucose metabolism in hippocampus may serve as biomarkers in trials.
• Patient Population: 
  • May benefit early in AD progression when astrocyte–neuron metabolic coupling becomes dysfunctional.
• Clinical Pathway:
  • CNS-active IDO1 inhibitors with known safety profiles (oncology) can be fast-tracked into Phase I/II AD trials.
  • Could complement anti-amyloid or anti-tau strategies by targeting metabolic resilience.

Key Take-Home Points

Minhas et al. shift the paradigm in AD research, demonstrating that targeting glial metabolic failure via IDO1 inhibition can restore hippocampal energy metabolism, synaptic plasticity, and cognition-even in the context of amyloid and tau pathologies. This opens an actionable translational avenue using existing IDO1 inhibitors to potentially mitigate cognitive decline in AD.

• Astrocyte metabolic support is critical-IDO1 overactivity disrupts glucose–lactate coupling and cognitive function.
• Pharmacologic IDO1 blockade (PF‑06840003) restores synaptic physiology and memory in preclinical models, independent of amyloid/tau load.
• Natural compounds like apigenin offer interesting in vitro activity, but clinical relevance is currently lacking.
• IDO1 inhibitors represent a novel, translational metabolic therapeutic strategy for Alzheimer's disease.