Brain cells most vulnerable to Alzheimer’s disease are first identified by scientists

Scientists have for the first time identified the brain cells most vulnerable to Alzheimer’s disease, in what has been termed the ‘holy grail’ of dementia studies.

The brain cells lie in an area known as the entoral cortex, which controls memory, navigation, and timekeeping, and are the first to be killed by the disease.

The researchers hope the findings can 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 are particularly susceptible to toxic clumps, or ‘tangles’, of a protein called tau that destroys them from within.

Co-senior author Professor Martin Kampmann of the Institute for Neurodegenerative Diseases said targeting them could stop the disease in its path.

Brain tissue analysis revealed that the specific group of cells disappear very early – followed by a similar subset in the superior frontal gyrus.

This is a gray matter area responsible for higher cognitive functions such as thinking, problem solving, planning, and working memory – used in the performance of tasks.

The findings published in Nature Neuroscience are a ‘holy grail’ of dementia research.

Prof Kampmann explained: ‘We know which neurons die first in other neurodegenerative diseases such as Parkinson’s disease and motor neuron disease, but not in Alzheimer’s disease.

“If we understood why these neurons are so vulnerable, we might be able to identify interventions that make them, and the brain as a whole, more resilient to the disease.”

Alzheimer’s disease is caused by tau and amyloid – another rogue protein that builds up into plaques or clumps outside of brain cells.

Tau has been referred to as the ‘bullet’. The team at California University in San Francisco says some brain cells collapse years before symptoms develop – opening a window of opportunity.

Co-senior author Prof. Lea Grinberg said, “The belief in the field is that once these waste proteins are there, it’s always ‘game over’ for the cell.

‘But our lab has found that that’s not the case.

Some cells end up with high levels of tau tangles well into the progression of the disease, but for some reason they 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 disease, while other cells seem to be able to withstand it for years, if not decades.’

The researchers studied tissue from two brain banks from dozens of people who had died in different stages of Alzheimer’s disease in the US and Brazil.

A technique called single-nucleus RNA sequencing then made it possible to group neurons based on patterns of gene activity.

In both the entoral cortex and the superior frontal gyrus, these vulnerable cells are distinguished by their expression of the protein RORB.

Under a microscope, they confirmed that these neurons do indeed die early in the disease. They are also more likely to collect tau tangles than neighbors without RORB.

Co-lead author Kun Leng, a PhD student in Prof Kampmann’s lab, said: “These findings support the view that tau build-up is a crucial motor of neurodegeneration.

‘But we also know from other data from the Grinberglab that not every cell that builds up these aggregates is equally susceptible.’

He plans to continue to look at factors underlying the selective vulnerability of RORB neurons using the gene editing technology the Kampmann lab has developed.

It is not clear whether RORB itself causes the selective vulnerability of the cells. But the protein provides a valuable new molecular ‘handle’.

This will help understand what predisposes these cells to Alzheimer’s disease – and how this can potentially be reversed.

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

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