Damage to white matter in the brain can trigger features associated with neurodegenerative disease, Cambridge researchers have discovered in a new study published today in the journal Nature.
A focal lesion in white matter...can trigger a coordinated response in connected grey matter, and that response is not simply damage. It is part of the brain's attempt to repair itself.
Ragnhildur Thóra Káradóttir
Until now, it was thought that neurodegenerative diseases such as Alzheimer's and Parkinson's disease were primarily associated with changes to the brain's grey matter.
This new finding suggests that treatments for neurodegenerative disease should target damage to the brain's white matter, in addition to grey matter which has been the focus until now.
The brain is equally divided into grey and white matter. Grey matter contains the brain's processing hubs, linked by an information highway - the white matter. Although white matter damage is a defining feature of multiple sclerosis and is also seen in neurodegeneration including Alzheimer's and Parkinson's disease, the consequences of white matter damage are not well understood.
The team, led by Professor Ragnhildur Thóra Káradóttir at the University of Cambridge's Stem Cell Institute, created localised damage to myelin - the main component of white matter - in a well-defined brain circuit and followed what happened over time. They found that small, localised myelin damage triggered a striking response in a connected, remote grey matter region. Neuronal activity fell, microglia - the brain's immune cells - became activated, and connections between neurons were lost.
Crucially, these changes were not permanent. After myelin was regenerated, neuronal activity recovered, connections between neurons returned, and the inflammatory response subsided.
The study also challenges a common assumption about brain inflammation. Grey matter inflammation is traditionally viewed as harmful. But here, the team found that this transient response was part of the repair process itself. When they prevented grey matter inflammation, myelin regeneration was impaired.
Conversely, when the team blocked myelin regeneration, the grey matter response did not resolve and instead became chronic. This suggests that failed myelin regeneration may help drive the persistent low-grade inflammation seen in neurodegenerative disease.
Káradóttir, who also holds a position at the University of Cambridge's Department of Veterinary Medicine, said: "We found that a focal lesion in white matter is not just a local event. It can trigger a coordinated response in connected grey matter, and that response is not simply damage. It is part of the brain's attempt to repair itself."
The finding is particularly relevant to multiple sclerosis, where white matter lesions, chronic inflammation and incomplete myelin regeneration are closely linked to disease progression.
The work offers a new framework for understanding how local white matter damage may contribute to wider dysfunction across the brain and, when regeneration fails, to sustained inflammation.
Professor Alasdair Coles, Professor of Clinical Neuroimmunology and Head of Clinical Neurosciences at the University of Cambridge, added: "These findings suggest that therapies enhancing myelin regeneration could help slow the progression of a potentially wide range of brain disorders."
Reference: de Faria Jr et al: 'Focal white matter lesions drive grey matter inflammation and synapse loss', Nature, 2026. DOI: 10.1038/s41586-026-10414-w
