A cellular cleanup process meant to protect neurons can instead pass harmful material to surrounding tissue.
By Shula Rosen
Israeli researchers have identified a mechanism in brain cells that may actively contribute to the spread of Alzheimer’s disease, overturning long-held assumptions about how neurons dispose of toxic proteins.
The findings, published this week in the journal Proceedings of the National Academy of Sciences, come from a study conducted at the Technion–Israel Institute of Technology and suggest that a cellular cleanup process meant to protect neurons can instead pass harmful material to surrounding tissue.
The research team, led by Professor Michael Glickman, dean of the Technion’s Faculty of Biology, and postdoctoral researcher Dr. Ajay Wagh, focused on a defective form of ubiquitin, a protein responsible for marking damaged proteins for destruction.
The mutated version, known as UBB+1, interferes with the normal disposal process and is known to accumulate in the brains of patients with Alzheimer’s disease.
Under typical conditions, neurons rely on a protein called p62 to manage this threat. P62 packages UBB+1 into membrane-bound vesicles, isolating the toxic protein and preventing immediate harm. Those vesicles usually follow one of two routes: transport to the lysosome, where the contents are broken down, or removal from the cell altogether.
According to the study, the second route carries unintended consequences. When vesicles containing UBB+1 are expelled into the fluid between brain cells, fragments of the toxic protein can escape and be taken up by neighboring neurons. This process, the researchers say, creates a pathway for the disease to move through brain tissue rather than remain confined to individual cells.
“We all want someone to take out the trash,” Glickman said. “But in this case, the cells are dumping their trash on their neighbors. Although this solves an acute problem for the individual cell, it may cause long-term damage to the entire tissue.”
The discovery helps explain how Alzheimer’s pathology can propagate even when individual neurons appear to be managing internal damage effectively.
It also opens new possibilities for earlier detection of the disease. The researchers suggest that measuring UBB+1-related markers in cerebrospinal fluid could provide warning signs before widespread neurological damage occurs.
Beyond diagnostics, the findings may inform more targeted treatment strategies aimed at correcting or blocking the faulty disposal pathway, rather than focusing solely on protein accumulation itself.
The study was supported by grants from the Israel Science Foundation and the European Research Council.
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