New research by UCLA Health and UC San Francisco has uncovered why certain brain cells are more resilient than others to the buildup of the toxic tau protein that is a hallmark of Alzheimer’s disease and related dementias.
For the study, published in Cell, researchers employed a novel CRISPR-based genetic screening approach in neurons derived from human stem cells. The team tested how knocking down individual genes affected the buildup of toxic tau clumps. Among more than 1,000 genes identified, the CRL5SOCS4 protein complex emerged as a key player that attaches molecular tags to tau, marking it for destruction by the cell's recycling machinery.
Importantly, subsequent analysis of brain tissue from Alzheimer's patients revealed that higher expression of CRL5SOCS4 components made neurons more likely to survive despite the accumulation of tau protein.
The study also revealed an unexpected connection between mitochondrial dysfunction and tau toxicity—when the researchers disrupted the cellular powerhouses that generate energy, they triggered the production of a specific tau fragment approximately 25 kilodaltons in size. This fragment closely resembles a biomarker found in the blood and spinal fluid of Alzheimer's patients known as NTA-tau.
The researchers demonstrated that this abnormal tau fragment changes how tau proteins clump together in test tube experiments, potentially influencing disease progression.
The findings provide several promising leads for therapeutic development. Enhancing CRL5SOCS4 activity could help neurons clear tau more effectively, while strategies to maintain proteasome function during stress might prevent the formation of toxic tau fragments.
“What makes this study particularly valuable is that we used human neurons carrying an actual disease-causing mutation,” said study first author Avi Samelson, assistant professor of neurology at UCLA Health. “These cells naturally have differences in tau processing, giving us confidence that the mechanisms we identified are relevant to human disease.”
Data from UCLA Health