IDO1 Enzyme Linked to Alzheimer's; New Drug PF068 Offers Hope

Alzheimer's disease (AD), a severe brain disorder disrupting thinking, cognition, and memory, affects more than 30 million individuals globally. The disease is commonly associated with the tangles caused by beta-amyloid protein (Aβ) and abnormal tau proteins. These pathological elements not only harm neural tissues and cells directly but also promote inflammation and impair neural function.

Recent evidence suggests that disruptions in glucose metabolism across various brain regions are linked to Aβ and tau tangles. Astrocytes, a type of brain cell, produce lactic acid through metabolic processes to support mitochondrial function and synaptic activity, which are critical for neuronal health. However, in individuals with AD, the overall brain glucose metabolism is diminished, weakening the supportive role of astrocytes and leading to cognitive and memory impairments.

A recent collaborative study published in Science by researchers from the Salk Institute for Biological Studies and Penn State University reveals that an enzyme called IDO1 breaks down tryptophan into kynurenine. When overactive, IDO1 activates the kynurenine pathway, reducing glucose metabolism in astrocytes and decreasing lactate production necessary for neuronal function, thereby exacerbating AD symptoms. Conversely, using IDO1 inhibitors in AD mice restored astrocyte function and improved memory.

In oncology, IDO1 has gained significant research interest, with clinical trials exploring IDO1 inhibitors' anticancer effects. A Phase 1 clinical trial demonstrated that the IDO1 inhibitor PF-068 (PF068) lowered kynurenine levels in glioblastoma patients, with nearly half showing disease control. This oncological research has expedited drug screening for new studies.

The research team tested the IDO1 inhibitor PF068 in a mouse model of AD. Results indicated that hippocampal glucose metabolism in these mice normalized, astrocyte function was restored, and memory improved significantly, suggesting that this potential cancer drug might also benefit AD treatment.

In their study, researchers first developed an AD mouse model exhibiting Aβ and tau protein pathologies and analyzed astrocytes in brain samples. Results showed elevated IDO1 mRNA levels and increased kynurenine production due to these proteins. Injecting PF068 into these mice decreased astrocytic IDO1 levels and inhibited downstream kynurenine pathway genes. Conversely, glycolytic-related gene expression increased. The PF068 treatment restored glycolytic intermediates, lactic acid production, and mitochondrial oxidative phosphorylation processes.

Further studies indicated that high IDO1 levels also disrupt glucose metabolism in the hippocampus, impair synaptic elasticity, and lead to memory function deficits. In memory tasks, untreated AD model mice performed poorly, whereas PF068-treated AD mice showed significant improvements in spatial and long-term memory.

Dr. Paras Minhas, co-first author of the study, noted that while current treatments targeting Aβ or tau protein tangles can slow disease progression, the new mouse study suggests that targeting brain metabolism may offer a route to further reverse disease progression. The findings underscore the critical role of lactic acid produced by astrocytes in supporting neuronal function.

Professor Katrin Andreasson, the study's corresponding author, stated that the IDO1 inhibitor improved AD symptoms in mice with Aβ and tau protein-associated AD models, indicating a broader potential application for AD treatment. The team plans to conduct clinical trials to evaluate whether IDO1 inhibitors can reduce cognitive and memory dysfunction in human AD patients.

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