The Culprit of Alzheimer's Disease Revealed: High Activity of IDO1 Enzyme Leads to Memory Collapse in 30 Million Patients; New Drug PF068 May Be the Key to Reversing It!

Alzheimer's disease (AD), a disease that severely impairs the brain's thinking, cognitive and memory functions, affects more than 30 million people worldwide. When discussing potential triggers for the disease, it is not difficult to think of the tangles caused by beta-amyloid protein (Aβ) and abnormal tau proteins. These two pathological factors not only cause direct damage to nerve tissue and cells, but also induce inflammation and destroy nerve function.

Further evidence suggests that the phenomenon associated with Aβ and tau tangles is A disorder of glucose metabolism in multiple regions of the brain. In the case of astrocytes, the cell produces lactic acid through metabolism to support mitochondrial activity and synaptic activity, which is essential for the healthy function of other neurons. However, the brain glucose metabolism of AD patients is generally decreased, and the supporting role of astrocytes is greatly weakened, further leading to cognitive and memory dysfunction.

In the latest issue of the journal Science, scientists from the Salk Institute for Biological Studies and Penn State University collaborated to discover that an enzyme called IDO1 is able to break down tryptophan into kynurenine. When IDO1 is overactive and activates the kynurenine pathway, it reduces glucose metabolism in astrocytes and reduces lactate production required by neurons, driving the progression of AD symptoms. In contrast, the use of IDO1 inhibitors in AD mice successfully restored astrocyte function and improved mouse memory.

In the field of oncology, IDO1 has become a hot molecule of research interest, and clinical trials have been conducted to test the anticancer effects of IDO1 inhibitors. For example, a Phase 1 clinical trial found that the IDO1 inhibitor PF-*** (PF068) reduced kynuridine levels in patients with glioblastoma, and nearly half of patients treated with PF068 had their disease under control.

Work in the field of oncology has saved valuable time for drug screening for new studies. The research team tried using the IDO1 inhibitor PF068 in a mouse model of AD, and the results showed that glucose metabolism in the hippocampus of the mice returned to normal levels, astrocyte function was restored, and memory function in AD mice was significantly improved, suggesting that this potential cancer treatment drug may also play a role in AD treatment.

In the experiment, the authors first constructed an AD mouse model with pathological characteristics of Aβ and tau proteins, and analyzed astrocytes in brain samples. The results showed that both pathological features caused a significant increase in the mRNA level of IDO1 in cells and increased kynurenine production. They then injected PF068 into mice, where not only was astrocyte IDO1 decreased, but genes in the downstream pathway of kynuridine were also inhibited.

On the contrary, the expression of glycolytic-related genes increased again. The authors found that with the addition of PF068, glycolytic intermediates, lactic acid and mitochondrial oxidative phosphorylation processes were restored.

In addition to astrocytes being affected, studies have shown that increased IDO1 also disrupts glucose metabolism in the hippocampus, impairs synaptic elasticity in this brain region, and causes impairment in memory function. In memory tasks, mice with AD models without any processing tended to perform worse. However, after treatment with IDO1 inhibitors, the performance of AD mice was significantly improved, and their spatial memory and long-term memory were restored.

Dr. Paras Minhas, co-first author of the study, noted that current treatment strategies targeting Aβ or tau protein tangles can be effective in slowing disease progression, but what the new study saw in mice shows that targeting brain metabolism holds promise for further reversing disease progression.

These findings support the idea that lactic acid produced by astrocytes plays an important role in supporting neuronal function. Professor Katrin Andreasson, corresponding author of the study, said that the IDO1 inhibitor improved AD symptoms in mice, both for Aβ and tau protein-associated AD mouse models, suggesting that it could work in A wide range of AD individuals. In the future, they plan to test the effects of IDO1 inhibitors in clinical trials in AD patients to see if the drug can also help reduce cognitive and memory dysfunction in humans. Alzheimer's disease (AD), a disease that severely impairs the brain's thinking, cognitive and memory functions, affects more than 30 million people worldwide. When discussing potential triggers for the disease, it is not difficult to think of the tangles caused by beta-amyloid protein (Aβ) and abnormal tau proteins. These two pathological factors not only cause direct damage to nerve tissue and cells, but also induce inflammation and destroy nerve function.

Further evidence suggests that the phenomenon associated with Aβ and tau tangles is A disorder of glucose metabolism in multiple regions of the brain. In the case of astrocytes, the cell produces lactic acid through metabolism to support mitochondrial activity and synaptic activity, which is essential for the healthy function of other neurons. However, the brain glucose metabolism of AD patients is generally decreased, and the supporting role of astrocytes is greatly weakened, further leading to cognitive and memory dysfunction.

In the latest issue of the journal Science, scientists from the Salk Institute for Biological Studies and Penn State University collaborated to discover that an enzyme called IDO1 is able to break down tryptophan into kynurenine. When IDO1 is overactive and activates the kynurenine pathway, it reduces glucose metabolism in astrocytes and reduces lactate production required by neurons, driving the progression of AD symptoms. In contrast, the use of IDO1 inhibitors in AD mice successfully restored astrocyte function and improved mouse memory.

In the field of oncology, IDO1 has become a hot molecule of research interest, and clinical trials have been conducted to test the anticancer effects of IDO1 inhibitors. For example, a Phase 1 clinical trial found that the IDO1 inhibitor PF-*** (PF068) reduced kynuridine levels in patients with glioblastoma, and nearly half of patients treated with PF068 had their disease under control.

Work in the field of oncology has saved valuable time for drug screening for new studies. The research team tried using the IDO1 inhibitor PF068 in a mouse model of AD, and the results showed that glucose metabolism in the hippocampus of the mice returned to normal levels, astrocyte function was restored, and memory function in AD mice was significantly improved, suggesting that this potential cancer treatment drug may also play a role in AD treatment.

In the experiment, the authors first constructed an AD mouse model with pathological characteristics of Aβ and tau proteins, and analyzed astrocytes in brain samples. The results showed that both pathological features caused a significant increase in the mRNA level of IDO1 in cells and increased kynurenine production. They then injected PF068 into mice, where not only was astrocyte IDO1 decreased, but genes in the downstream pathway of kynuridine were also inhibited.

On the contrary, the expression of glycolytic-related genes increased again. The authors found that with the addition of PF068, glycolytic intermediates, lactic acid and mitochondrial oxidative phosphorylation processes were restored.

In addition to astrocytes being affected, studies have shown that increased IDO1 also disrupts glucose metabolism in the hippocampus, impairs synaptic elasticity in this brain region, and causes impairment in memory function. In memory tasks, mice with AD models without any processing tended to perform worse. However, after treatment with IDO1 inhibitors, the performance of AD mice was significantly improved, and their spatial memory and long-term memory were restored.

Dr. Paras Minhas, co-first author of the study, noted that current treatment strategies targeting Aβ or tau protein tangles can be effective in slowing disease progression, but what the new study saw in mice shows that targeting brain metabolism holds promise for further reversing disease progression.

These findings support the idea that lactic acid produced by astrocytes plays an important role in supporting neuronal function. Professor Katrin Andreasson, corresponding author of the study, said that the IDO1 inhibitor improved AD symptoms in mice, both for Aβ and tau protein-associated AD mouse models, suggesting that it could work in A wide range of AD individuals. In the future, they plan to test the effects of IDO1 inhibitors in clinical trials in AD patients to see if the drug can also help reduce cognitive and memory dysfunction in humans.