Scientists have identified brain cells most vulnerable to Alzheimer’s disease for the first time, in what is referred to as the “Holy Grail” of studies of dementia.
The brain cells are located in an area known as the entorhinal cortex, which controls memory, movement and perception of time, and is the first to die from disease.
Scientists hope the results can be used to develop a new, more targeted approach, to develop treatments to slow or prevent the spread of Alzheimer’s disease.
Brain cells are particularly vulnerable to toxic clumps, or “tangles,” from a protein called tau, which destroys them from the inside.
Associate senior author Professor Martin Kampmann of the Institute of Neurodegenerative Diseases said targeting them could stop the disease in its tracks.
An analysis of brain tissue found that the specific set of cells disappears very early – followed by a similar subset in the anterior superior gyrus.
This is an area of gray matter responsible for higher-order cognitive functions – such as reasoning, problem solving, planning, and working memory – used to carry out tasks.
Professor Kampmann explained: “We know which neurons are the first to die in other neurodegenerative diseases, such as Parkinson’s disease and motor neuron disease – but not Alzheimer’s disease. And the brain as a whole is more resistant to disease. “
Alzheimer’s disease is caused by the tau protein and amyloid – another protein formed in plaques or clumps outside brain cells.
The “tau” is described as the “bullet”. The team at the University of California, San Francisco, says some brain cells give up years before symptoms appear – which opens up a “window of opportunity”.
“The belief in this field was simply because there were these neglected proteins, and the cell is always game over,” said Professor Leah Greenberg, lead author of the study. “Good at disease progression, but for some reason it does not die. It has become an urgent question for us to understand the specific factors that make some cells selectively susceptible to Alzheimer’s disease, while other cells seem to be able to resist them for years, if not decades.”
Researchers studied brain tissue of dozens of people who died in various stages of Alzheimer’s disease, in the United States and Brazil.
A technique called single-core RNA sequencing made it possible to assemble neurons based on patterns of genetic activity.
In both the endocortex and the superior frontal gyrus, these vulnerable cells were characterized by their expression of a protein called RORB.
Under a microscope, they confirmed that these neurons were, in fact, dying early in the disease. It also combines a “tau” interlacing without RORB.
Senior co-author Kun Ling, a PhD student in Professor Kampmann’s lab, said: “These results support the view that the accumulation of tau is a critical driver of neurodegeneration. But we also know from other data that not every cell consisting of these clumps is equally exposed. “.
He plans to continue researching the factors behind the selective vulnerability of RORB neurons, using a gene-editing technique developed by Kampmann’s lab.
It is not clear if RORB itself causes selective impairment of cells. But the protein provides a valuable new molecular “knob”. This will help understand what makes these cells vulnerable to Alzheimer’s disease – and how it can be reversed.
“Our discovery of the molecular identifier of these weak cells selectively gives us the opportunity to study in detail exactly why they succumb to the pathology of Tao – and what can be done to make them more resilient. This will be an approach,” said senior co-author Kun Ling, of the University of California, San Francisco. A completely new and more targeted development of treatments to slow or prevent the spread of Alzheimer’s disease. “
The study results are published in Nature Neuroscience.
Source: Daily Mail