Researchers at the Technion–Israel Institute of Technology have uncovered a surprising mechanism that may help explain how Alzheimer’s disease spreads through the brain. A cellular system designed to protect neurons by removing toxic proteins may, under certain conditions, actually facilitate the spread of those proteins to neighboring cells—accelerating disease progression.

The study, published in PNAS, was led by Prof. Michael Glickman, Dean of the Technion’s Faculty of Biology, together with Dr. Ajay Wagh. The researchers focused on UBB+1, a defective and toxic form of ubiquitin—a protein normally responsible for marking damaged proteins for degradation.

In healthy cells, toxic proteins are typically broken down internally. However, the team discovered that brain cells sometimes export UBB+1 outside the cell instead of destroying it. This process is mediated by p62, a protein involved in autophagy, the cell’s self-cleaning system. While p62 can direct toxic proteins to the cell’s recycling center (the lysosome), it can also package them into vesicles that are secreted into the extracellular brain fluid.

Once outside the cell, fragments of UBB+1 can leak into neighboring neurons, potentially spreading toxic protein aggregates across brain tissue. This finding may help explain how Alzheimer’s, which can begin in isolated neurons, gradually affects large regions of the brain.

“We all want someone to take out the trash,” says Prof. Glickman, “but in this case, the cells are dumping their trash on their neighbors.”

The discovery could pave the way for earlier diagnosis of Alzheimer’s through fluid biomarkers and for the development of targeted, personalized treatments.

The study was supported by the Israel Science Foundation (ISF) and the European Research Council (ERC).

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