Brain cells vulnerable to Alzheimer’s Disease have been identified for the first time, in a breakthrough scientists hope could lead to targeted treatments to boost the brain’s resilience.
It has so far remained unknown in Alzheimer’s research why some brain cells succumb to the disease years before symptoms first appear, while others seem unaffected by the degeneration surrounding them until the disease’s final stages.
Now, in a groundbreaking study, the neurons that are among the first victims of the disease – accumulating toxic ‘tangles’ and dying off earlier than neighbouring cells – have been identified for the first time.
“We know which neurons are first to die in other neurodegenerative diseases like Parkinson’s disease and ALS, but not Alzheimer’s,” says co-senior author Martin Kampmann, associate professor in the UCSF Institute for Neurodegenerative Diseases.
“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 researchers have long studied why certain cells are more prone to producing the toxic tangles of the protein known as tau, whose spread through the brain drives widespread cell death and resulting progressive memory loss, dementia, and other symptoms.
But researchers have not looked closely at whether all cells are equally vulnerable to the toxic effects of these protein accumulations.
“The belief in the field has been that 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,” said Lea Grinberg, senior co-author and associate professor in the UCSF Memory and Ageing Centre.
“Some cells end up with high levels of tau tangles well into the progression of the disease, but for some reason don’t die.
“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.”
To identify selectively vulnerable neurons, the researchers studied brain tissue from people who had died at different stages of Alzheimer’s disease, obtained from the UCSF Neurodegenerative Disease Brain Bank and the Brazilian BioBank for Ageing Studies.
The São Paulo-based biobank collects tissue samples from a broad population of deceased individuals, including many without a neurological diagnosis whose brains nevertheless show signs of very early-stage neurodegenerative disease, which is otherwise very difficult to study in humans.
The team studied tissue from ten donor brains using a technique called single-nucleus RNA sequencing, which let them group neurons based on patterns of gene activity.
In a brain region called the entorhinal cortex, one of the first areas attacked by Alzheimer’s, the researchers identified a particular subset of neurons that began to disappear very early on in the disease.
Later in the course of the disease, the researchers found, a similar group of neurons were also first to die off when degeneration reached the brain’s superior frontal gyrus.
“These findings support the view that tau buildup is a critical driver of neurodegeneration, but we also know from other data from the that not every cell that builds up these aggregates is equally susceptible,” adds researcher Kun Leng.
“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.”
