Scientists have identified the brain cells that are most vulnerable to Alzheimer’s disease for the first time, in what’s being referred to as the ‘holy grail’ of dementia studies.
The brain cells lie in a region known as the entorhinal cortex, which controls memory, navigation and time perception, and are the first to be killed off by the disease.
The researchers hope the findings could be used to develop a new and much more targeted approach to developing therapies to slow or prevent the spread of Alzheimer’s disease.
The brain cells lie in a region known as the entorhinal cortex, which controls memory, navigation and time perception, and are the first to be killed off by the disease
The brain cells are particularly prone to toxic clumps, or ‘tangles’, of a protein called tau that destroys them from within.
Co-senior author Professor Martin Kampmann, of Institute for Neurodegenerative Diseases, said targeting them could stop the disease in its tracks.
Analysis of brain tissue found the specific group of cells disappear very early on – followed by a similar subset in the superior frontal gyrus.
This is an area of grey matter responsible for higher cognitive functions such as thinking, problem solving, planning and working memory – used in the execution of tasks.
The findings published in Nature Neuroscience are a ‘holy grail’ of dementia research.
Prof Kampmann explained: ‘We know which neurons are first to die in other neurodegenerative diseases like Parkinson’s disease and motor neurone disease – but not Alzheimer’s.
‘If we understood why these neurons are so vulnerable, maybe we could identify interventions that could make them, and the brain as a whole, more resilient to the disease.’
Alzheimer’s is caused by tau and amyloid – another rogue protein that builds into plaques, or clumps, outside brain cells.
Tau has been described as the ‘bullet’. The team at California University in San Francisco say some brain cells succumb years before symptoms develop – opening a ‘window of opportunity’.
Co-senior author Prof Lea Grinberg said: ‘The belief in the field has been once these trash proteins are there, it’s always ‘game over’ for the cell.
‘But our lab has been finding that that is not the case.
‘Some cells end up with high levels of tau tangles well into the progression of the disease, but for some reason don’t die.
Analysis of brain tissue found the specific group of cells disappear very early on – followed by a similar subset in the superior frontal gyrus (stock image)
Somebody is diagnosed with dementia every three seconds. It is the biggest killer in some wealthier countries – and is completely untreatable (stock image)
‘It has become a pressing question for us to understand the specific factors that make some cells selectively vulnerable to Alzheimer’s pathology, while other cells appear able to resist it for years, if not decades.’
The researchers studied tissue from two brain banks of dozens of people who had died at different stages of Alzheimer’s in the US and Brazil.
A technique called single-nucleus RNA sequencing enabled then to group neurons based on patterns of gene activity.
In both the entorhinal cortex and the superior frontal gyrus, these vulnerable cells were distinguished by their expression of a protein called RORB.
Under a microscope, they confirmed these neurons do in fact die off early on in the disease. They also accumulate tau tangles earlier than neighbours without RORB.
Co-first author Kun Leng, a PhD student in Prof Kampmann’s lab, said: ‘These findings support the view tau build-up is a critical driver of neurodegeneration.
‘But we also know from other data from the Grinberg lab that not every cell that builds up these aggregates is equally susceptible.’
He plans to continue looking at factors underlying RORB neurons’ selective vulnerability using gene-editing technology the Kampmann lab has developed.
It’s not clear whether RORB itself causes the cells’ selective vulnerability. But the protein provides a valuable new molecular ‘handle’.
This will help understand what makes these cells susceptible to Alzheimer’s – and how it could potentially be reversed.
Co-first author Kun Leng, of California University in San Francisco, said: ‘Our discovery of a molecular identifier for these selectively vulnerable cells gives us the opportunity to study in detail exactly why they succumb to tau pathology – and what could be done to make them more resilient.
‘This would be a totally new and much more targeted approach to developing therapies to slow or prevent the spread of Alzheimer’s disease.’