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A groundbreaking study led by USC Stem Cell researchers has found a way to reduce toxic tau buildup, a major contributor to Alzheimer’s disease and related dementias. Instead of targeting glutamate, a key brain chemical linked to memory and learning, the study identifies a new gene-based strategy that helps clear harmful tau proteins from brain cells.
The Problem: How Glutamate Fuels Tau Buildup
Glutamate is an essential neurotransmitter that helps regulate mood, memory, and brain function. However, too much glutamate activity can trigger a toxic buildup of tau proteins, which contribute to neurodegeneration, nerve cell death, and diseases like Alzheimer’s.
The researchers, led by Dr. Justin Ichida at USC’s Keck School of Medicine, explain that directly reducing glutamate is not a viable treatment.
“Limiting glutamate can cause serious side effects, including memory problems, motor deficits, or even loss of consciousness,” says Ichida.
Instead, the team took a different approach—one that boosts the brain’s natural ability to clear toxic proteins rather than reducing glutamate itself.
A New Approach: Boosting the Brain’s Cleaning System
The researchers studied human brain organoids (miniature lab-grown brain models) made from stem cells of both healthy individuals and patients with tau-related neurodegenerative diseases. When exposed to glutamate, these organoids—especially those from diseased patients—showed toxic tau buildup and nerve cell death.
The same harmful effects were seen in mice with a tau mutation, which is known to cause a form of dementia.
To find a solution, the team screened for genes that respond to glutamate and identified a key player: KCTD20. When the scientists suppressed this gene in both brain organoids and mice, tau buildup dramatically decreased, and nerve cells remained healthy despite exposure to glutamate.
Further experiments revealed why: blocking KCTD20 activated lysosomes, the brain’s natural waste disposal system. Lysosomes wrapped around the toxic tau proteins and expelled them, effectively clearing them from brain cells.
Why This Discovery Matters
This research suggests that boosting the brain’s ability to clear tau proteins could be a powerful new strategy for treating Alzheimer’s and similar diseases. Instead of risking harmful side effects by lowering glutamate, targeting KCTD20 could enhance the brain’s natural defenses.
“Our study highlights enhancing tau clearance as a promising therapeutic strategy,” says Dr. Jesse Lai, co-author of the study.
Dr. Joshua Berlind, another researcher on the team, adds: “This could lead to more effective and targeted treatments for Alzheimer’s and other neurodegenerative diseases.”
What’s Next?
While this discovery is still in the experimental stage, it opens up exciting possibilities for future drug development. If scientists can create a therapy that suppresses KCTD20 or boosts lysosome activity, it could help slow or even prevent Alzheimer’s.
With further research, this innovative approach could change the way we treat neurodegenerative diseases, offering hope to millions of patients and their families.
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The research findings can be found in Neuron.
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