Stem cell scientists from the University of Southern California (USC) and elsewhere have found a way to potentially clear out the buildup of tau protein in the brain, which is associated with the development of tauopathies like Alzheimer’s disease. Details of the study are provided in a newNeuron paper titled, “KCTD20 suppression mitigates excitotoxicity in tauopathy patient organoids.”
The research focuses on the response to glutamate, an important neurotransmitter for regulating memory, moods, and other activities in the brain. For the study, the scientists used lab mice and brain organoids produced from stem cells derived from healthy people as well as from patients with neurodegenerative diseases related to tau toxicity.
When exposed to glutamate, the organoids—particularly the ones derived from patients with neurodegenerative diseases—exhibited a toxic buildup of tau protein as well as neurodegeneration and nerve cell death. Transgenic mice with a mutation in tau, which causes a common form of dementia, displayed similar pathologies when exposed to the neurotransmitter as well.
Scientists have tried to target glutamate toxicity as a treatment strategy for neurodegenerative diseases with “mixed results in clinical trials,” said Justin Ichida, PhD, corresponding author on the study and an associate professor of stem cell biology and regenerative medicine at USC’s Keck School of Medicine. “One challenge is that directly limiting the activity of glutamate, a key neurotransmitter, can have negative consequences, such as motor or memory deficits or even reduced consciousness.”
Ichida and his colleagues took a different approach. Specifically, they screened samples for genes that respond to glutamate and identified one called KCTD20. When researchers suppressed the activity of this gene using a genome-wide CRISPR interference screen in both the mice and brain organoids, they found that glutamate did not have the same ill effects in terms of either tau buildup or neurodegeneration.
Looking deeper, the team discovered that suppressing KCTD20’s activity activated lysosomes in the organoids’ cells that enveloped the tau proteins and expelled them. The findings point “toward enhancing tau protein clearance as an important therapeutic strategy, rather than aiming to limit glutamate activity,” said Jesse Lai, PhD, one of the authors on the study and a former postdoctoral student in the Ichida Lab.