Scientists identify brain cells most vulnerable to Alzheimer’s disease for first time

Scientists have identified the most vulnerable brain cells to Alzheimer’s disease for the first time, in what is known as the “holy grail” of dementia studies.

Brain cells are found in a region known as the entorinal cortex, which controls memory, navigation, and time perception, and are the first to die from the disease.

The researchers hope the findings could be used to develop a new, much more specific approach to developing therapies to slow or prevent the spread of Alzheimer’s disease.

Brain cells are particularly prone to toxic groups, or “messes,” of a protein called tau that destroys them from within.

Co-author Professor Martin Kampmann of the Institute for Neurodegenerative Diseases said addressing them could stop the disease.

Brain tissue analysis found that the specific group of cells disappeared very soon, followed by a subset similar to the upper frontal gyrus.

This is an area of ​​gray matter responsible for higher cognitive functions such as thinking, problem solving, planning, and working memory, which is used in the execution of tasks.

The findings published in Nature Neuroscience are a “holy grail” of dementia research.

Professor Kampmann explained: “We know which neurons die for the first time in other neurodegenerative diseases such as Parkinson’s disease and motor neurons, but not Alzheimer’s.

“If we understood why these neurons are so vulnerable, perhaps we could identify the interventions that could make them, and the brain in general, more resistant to the disease.”

Alzheimer’s is caused by tau and amyloid, another rogue protein that builds up in plaques or clusters outside of brain cells.

Tau has been described as the “bullet.” The University of California, San Francisco team says some brain cells succumb years before symptoms develop, opening a “window of opportunity.”

Co-senior teacher Professor Lea Grinberg said, “The belief in the field has been once these garbage proteins are there, it’s always‘ finished ’for the cell.

But our lab has been discovering that this is not the case.

“Some cells end up with high levels of tangled tau until the disease progresses, but for some reason they do not die.

“It has become an urgent question to understand the specific factors that make some cells selectively vulnerable to Alzheimer’s disease, while other cells appear to be able to resist it for years, if not decades. “.

The researchers studied tissues from two brain banks of dozens of people who had died at different stages of Alzheimer’s in the U.S. and Brazil.

A technique called single-core RNA sequencing then allowed neurons to be grouped based on patterns of gene activity.

In both the entorinal cortex and the superior frontal gyrus, these vulnerable cells were distinguished by their expression of a protein called RORB.

Under the microscope, they confirmed that these neurons in fact die early in the disease. They also accumulate tau tangles before neighbors without RORB.

Co – author Kun Leng, a doctoral student in Professor Kampmann ‘s laboratory, said: “These results support the view that accumulation is a critical factor in neurodegeneration.

“But we also know from other data from Grinberg’s lab that not all cells that accumulate these aggregates are equally susceptible.”

He plans to continue studying the factors underlying the selective vulnerability of RORB neurons using the gene editing technology developed by the Kampmann Laboratory.

It is unclear whether RORB itself causes the selective vulnerability of cells. But the protein provides a valuable molecular “handle”.

This will help you understand what makes these cells susceptible to Alzheimer’s and how it could be reversed.

Co-author Kun Leng of the University of California at San Francisco said: “Our discovery of a molecular identifier for these selectively vulnerable cells gives us the opportunity to study in detail why they succumb to tau pathology. , and what could be done to make them more resilient.

“This would be a whole new and much more specific approach to developing therapies to slow or prevent the spread of Alzheimer’s disease.”