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Role of glucose metabolism in Alzheimer’s disease

Astrocytes (center) play a crucial role in supporting neurons (top). ART-ur / Shutterstock

In Alzheimer’s disease (AD), misfolded amyloid β (Aβ) and tau proteins accumulate in the brain. This leads to the progressive loss of connections between neurons. At the same time, glucose metabolism declines in certain types of brain cells, called astrocytes and microglia. One function of astrocytes is to help ensure that neurons have enough energy to support their activity. Astrocytes do this by breaking down glucose into lactate and exporting it to neurons. Neurons can then use the lactate as fuel.

Recent research has implicated an enzyme in astrocytes, called indoleamine-2,3-dioxygenase 1 (IDO1), in AD. A team of researchers, led by Dr. Katrin Andreasson at Stanford University, examined how IDO1 affects glucose metabolism in astrocytes. They also looked at how IDO1 and glucose metabolism relate to AD pathology and brain function. The study, which was funded in part by NIH, appeared in Science on August 23, 2024.

The team found that Aβ and tau increased IDO1 levels and activity in astrocytes from both mice and humans. The proteins also suppressed the conversion of glucose to lactate. Inhibiting IDO1 with a drug, or turning off the gene that encodes IDO1, restored lactate production in the presence of Aβ and tau.

The hippocampus is the brain region responsible for learning and memory. In various mouse models of AD, the team found that lactate production in the hippocampus was suppressed. The mice also had impaired spatial memory and low hippocampal synaptic plasticity (the ability of connections between neurons to strengthen over time). Inhibiting IDO1 restored all three of these to normal levels. But inhibiting IDO1 had no effect on synaptic plasticity when neurons were blocked from importing lactate. This suggests that lactate in the hippocampus is important for spatial memory and plasticity.

To see if these findings also applied to AD in humans, the team derived stem cells from people with and without late-onset AD. They then induced the stem cells to form astrocytes and neurons. Glucose metabolism and lactate production were reduced in the astrocytes derived from AD patients. The astrocytes also didn’t effectively transfer lactate to neurons. Inhibiting IDO1 restored lactate production in the astrocytes and its uptake by neurons to normal levels.

The findings suggest that Aβ and tau boost IDO1 activity in astrocytes. This reduces glucose metabolism and lactate production. The loss of lactate, in turn, deprives neurons of an important fuel source.

Restoring lactate production by inhibiting IDO1 might prevent or even reverse the cognitive effects of AD. IDO1 inhibitors have already been developed for cancer treatment and might be repurposed for AD treatment.

“We also can’t overlook the fact that we saw this improvement in brain plasticity in mice with both amyloid and tau mice models,” Andreasson notes. “These are completely different pathologies, and the drugs appear to work for both. That was really exciting to us.”

That suggests that different pathologies may damage neurons via a common mechanism. Thus, this treatment approach could potentially work not only for AD, but for other neurodegenerative diseases as well.

—by Brian Doctrow, Ph.D.