Targeting Lysosomes Could Halt Tau Accumulation in Alzheimer’s
Researchers found that blocking KCTD20 prevents glutamate-induced tau buildup.
Glutamate, a key neurotransmitter involved in brain function, plays a crucial role in processes such as mood regulation and memory formation. However, research has also linked glutamate to the toxic accumulation of tau protein – a hallmark of neurodegenerative diseases like Alzheimer’s. A recent study led by scientists at USC Stem Cell, published in Neuron, investigates a new strategy to counteract these damaging effects.
Glutamate
A neurotransmitter that plays a vital role in brain function, particularly in learning and memory. However, excessive glutamate activity has been linked to neurotoxicity.Tau protein
A protein that stabilizes structures within nerve cells. In certain neurodegenerative diseases, tau becomes abnormally accumulated, forming toxic clumps that disrupt cell function.Investigating tau toxicity in lab models
To explore how glutamate contributes to tau-related neurodegeneration, researchers used both genetically modified mice and human brain organoids—miniature brain-like structures derived from stem cells. These organoids were developed from healthy individuals and patients with neurodegenerative diseases associated with tau toxicity.
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Subscribe for FREEWhen exposed to glutamate, the organoids – particularly those derived from patients – exhibited a buildup of tau protein, nerve cell death and other signs of neurodegeneration. Similarly, mice carrying a tau mutation associated with dementia displayed comparable pathological features.
A gene-based approach to mitigating toxicity
Many drug candidates have been developed to address glutamate-induced neurodegeneration, but they have had limited success in clinical trials. One challenge is that directly reducing glutamate activity can cause adverse effects, including impairments in memory and motor function. To identify an alternative approach, the research team screened for genes that respond to glutamate exposure and identified KCTD20 as a key player.
Suppressing KCTD20 in both the organoids and mice prevented glutamate from triggering tau accumulation and neurodegeneration. Further experiments showed that blocking this gene’s activity activated lysosomes—cellular compartments responsible for breaking down waste. As a result, toxic tau proteins were encapsulated and expelled from cells, reducing their harmful buildup.
Lysosomes
Cellular structures that act as waste disposal systems by breaking down and removing unwanted proteins and cellular debris.Implications for future treatments
This study highlights the potential of targeting tau protein clearance mechanisms rather than directly modulating glutamate levels. By enhancing lysosomal activity, researchers may be able to develop new therapeutic strategies for tau-related neurodegenerative diseases, including Alzheimer’s.
Reference: Berlind JE, Lai JD, Lie C, et al. KCTD20 suppression mitigates excitotoxicity in tauopathy patient organoids. Neuron. 2025:S089662732500114X. doi: 10.1016/j.neuron.2025.02.001
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