Existing cancer drugs have shown promise as a future treatment for Alzheimer's disease, new research has found.
The drugs work by restoring healthy sugar metabolism in the brains of Alzheimer's patients and may offer effective treatment across a range of different neurodegenerative disorders.
Alzheimer's disease affects roughly 5.8 million Americans, according to the Centers for Disease Control and Prevention. The progressive disease is the most common form of dementia and is associated with memory loss and cognitive decline in regions of the brain involved in thought, memory and language.
Today, there is no known cure for Alzheimer's, although scientists believe that it is caused by the abnormal buildup of proteins in and around brain cells. However, alongside this protein buildup, Alzheimer's patients also see sustained declines in their brain's ability to break down the sugar glucose.
"Glucose metabolism declines significantly in Alzheimer's disease," the study's senior author, Katrin Andreasson, a neurologist at the Stanford School of Medicine and member of the Wu Tsai Neurosciences Institute, told Newsweek. "In fact, we sometimes use this measure to diagnose patients with Alzheimer's."
Without effective sugar metabolism, the brain does not have enough energy to fuel itself, resulting in impaired thinking and memory—two major hallmarks of Alzheimer's.
In particular, higher levels of an enzyme called indoleamine-2,3,-dioxygenase 1 (IDO1) have been reported in the brains of patients with multiple neurodegenerative disorders, which researchers believe may be a direct consequence of the abnormal protein clumps that buildup in the brains of Alzheimer's patients.
IDO1 is a molecular machine that is thought to play an important role in regulating our immune systems, but it can also disrupt glucose metabolism in out cells.
In a new study, published in the journal Science, Andreasson and colleagues demonstrated that inhibiting IDO1, and the subsequent production of kynurenine, was able to improve cognitive function in lab mice with Alzheimer's-like brain conditions by restoring healthy glucose metabolism in their brain cells.
"We were surprised that these metabolic improvements were so effective at not just preserving healthy synapses, but in actually rescuing behavior," Andreasson said. "The mice performed better in cognitive and memory tests when we gave them drugs that block [IDO1]."
Because of its role in immune system regulation, IDO1 inhibitors have already been developed for cancer therapy, to support our immune systems in tackling tumors. However, these same drugs may also help patients with Alzheimer's.
"Depending on whether they are deemed safe in ad patients, they could potentially be repurposed for Alzheimer's disease," Andreasson said.
She added that targeting energy metabolism in this way was very different to the majority of existing Alzheimer's therapy avenues, which target the abnormal protein clumps rather than changes that occur in the brain cells themselves.
"Improving energy metabolism and glucose metabolism by [brain cells] is a new approach," she said.
Because glucose metabolism is disrupted in several different neurodegenerative disorders, this treatment strategy also shows promise for other brain conditions.
"The beneficial effect on brain metabolism by IDO1 inhibition cuts across different types of pathology," Andreasson said.
"It is exciting to think that this may be a more general mechanism that could be targeted in other neurodegenerative disorders, like Parkinson's disease, where you have accumulation of a-synuclein, or ALS, where there is accumulation of tdp-43."
The team now hope to test IDO1 inhibitors in human Alzheimer's patients to see if they show similar symptom improvements.
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References
Minhas, P. S., Jones, J. R., Latif-Hernandez, A., Sugiura, Y., Durairaj, A. S., Wang, Q., Mhatre, S. D., Uenaka, T., Crapser, J., Conley, T., Ennerfelt, H., Jung, Y. J., Liu, L., Prasad, P., Jenkins, B. C., Ay, Y. A., Matrongolo, M., Goodman, R., Newmeyer, T., Heard, K., Kang, A., Wilson, E. N., Yang, T., Ullian, E. M., Serrano, G. E., Beach, T. G., Wernig, M., Rabinowitz, J. D., Suematsu, M., Longo, F. M., McReynolds, M. R., Gage, F. H., & Andreasson, K. I. (2024). Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies. Science, 385(6711). http://dx.doi.org/10.1126/science.abm6131
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