Scientists have discovered why certain brain cells are better at resisting Alzheimer’s disease, a breakthrough that could open the door to new treatments.
The research, led by teams at UCLA Health and the University of California San Francisco, reveals how some neurons can protect themselves from toxic protein buildup that damages the brain.
A key feature of Alzheimer’s and related diseases is the accumulation of a protein called tau. In healthy brains, tau helps support the structure of nerve cells.
But in disease, it forms harmful clumps that kill neurons and interfere with memory and thinking.
One mystery has puzzled scientists for years: why do some brain cells fill up with tau while others remain relatively unharmed?
To investigate, researchers grew human brain cells in the lab using stem cells and then used a powerful gene-editing method called CRISPR to switch off thousands of genes one by one.
This allowed them to see which genes affected how much tau built up inside the cells.
By scanning nearly the entire human genome, they identified many processes that influence tau levels.
One of the most important discoveries was a protein group known as CRL5SOCS4.
This complex acts like a cleanup crew, tagging tau so the cell’s recycling system can break it down. Brain tissue from people with Alzheimer’s showed that neurons with higher levels of this protein complex were more likely to survive, even when tau was present.
This suggests that boosting the activity of this natural defense system might help protect the brain.
The study also uncovered a surprising link between energy problems in cells and tau damage. When researchers disrupted mitochondria, the structures that produce energy, the cells created an unusual fragment of tau protein.
This fragment closely resembles a marker found in the blood and spinal fluid of Alzheimer’s patients. The scientists believe this happens when cells experience oxidative stress, a type of damage that becomes more common with aging.
Under stress, the cell’s protein recycling machinery—called the proteasome—does not work properly. Instead of destroying tau completely, it produces harmful pieces that may worsen disease progression. Laboratory experiments showed that this abnormal tau fragment changes how tau clumps together, potentially speeding up brain damage.
The findings point to several possible strategies for future treatments. Strengthening the CRL5SOCS4 cleanup system could help brain cells remove toxic proteins more effectively. Protecting the cell’s recycling machinery during times of stress might also prevent the formation of dangerous tau fragments.
Importantly, the research used human neurons carrying real disease-causing mutations, making the results more relevant to patients. The team also discovered several unexpected biological pathways that may influence tau buildup, offering additional clues for scientists to explore.
Although more work is needed before these discoveries can lead to new therapies, the study provides a clearer picture of why some brain cells withstand Alzheimer’s damage while others cannot.
Understanding these natural defense mechanisms brings researchers one step closer to slowing or even preventing this devastating disease.
