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

Scientists have first identified the brain cells that are most vulnerable to Alzheimer’s disease, called the ‘holy grail’ of dementia studies.

The brain cells lie in an area known as the entorhinal cortex, which controls memory, navigation and time perception, and is the first to be killed by the disease.

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

The brain cells are particularly prone to toxic tufts, or ‘tangles’, of a protein called tau that destroys them from within.

The co-senior author, Professor Martin Kampmann, of the Institute of Neurodegenerative Diseases, said they can stop the disease in its tracks if they are targeted.

Analysis of brain tissue found that the specific group of cells disappeared very early – followed by a similar subgroup in the superior frontal gyrus.

It is an area of ​​gray matter that is responsible for higher cognitive functions such as thinking, problem solving, planning and working memory – which are 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 die first in other neurodegenerative diseases such as Parkinson’s disease and motor neurone disease, but not Alzheimer’s.

“If we understand why these neurons are so vulnerable, we can identify interventions that can 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 up outside the brain cells in plates or clumps.

Tau is described as the ‘bullet’. The team at the University of California, San Francisco says that some brain cells succumb years before symptoms develop – which opens a ‘window of opportunity’.

Fellow senior author, Prof Lea Grinberg, said: ‘The faith in the field was once these trash proteins were there, it’s always’ game over’ for the cell.

‘But our lab determined that was not the case.

‘Some cells end up with a high level of tau far in the progression of the disease, but do not die for some reason.

“It has become an urgent question for us to understand the specific factors that make some cells vulnerable to Alzheimer’s pathology, while other cells appear to be able to withstand it for years or decades.”

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

A technique called single-core RNA sequencing could then group neurons based on patterns of gene activity.

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

Under a microscope, they confirmed that these neurons die early in the disease. They also accumulate clutter earlier than neighbors without RORB.

Co-first author Kun Leng, a PhD student in Prof Kampmann’s laboratory, said: ‘These findings support the view that the buildup is a critical cause of neurodegeneration.

“But we also know from other data from the Grinberg laboratory that not every cell that makes up these aggregates is equally susceptible.”

He plans to continue looking at factors underlying the selective vulnerability of RORB neurons using no-processing technology developed by the Kampmann laboratory.

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 to understand what makes these cells susceptible to Alzheimer’s – and how they can possibly be reversed.

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

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