Scientists ID Brain Cells Most Vulnerable to Alzheimer’s Disease

Studying brain tissue of 10 donors who had varying degrees of Alzheimer’s disease when they died, scientists discovered neurons in the parts of the brain that handle memory, navigation and self-awareness are early targets of the disease.

PET scan of a human brain with Alzheimer’s disease. (Photo by US National Institute on Aging, Alzheimer’s Disease Education and Referral Center)

(CN) — Different parts of the brain are more susceptible to the effects of Alzheimer’s disease than others, and according to a study released Monday the specific at-risk neurons have now been identified for the first time — promising hope that they can be treated to become more resilient to the illness.

Conducted by a group of molecular biologists and neuropathologists from the University of California San Francisco Weill Institute for Neurosciences, this interdisciplinary study published Jan. 10, 2021 in the journal Nature Neuroscience, tackled the long-lived question of why Alzheimer’s alters specific parts of the brain before others, resulting in a worsening of symptoms over time. 

“We know which neurons are first to die in other neurodegenerative diseases like Parkinson’s disease and ALS, but not Alzheimer’s,” said co-senior author Martin Kampmann, an associate professor in the UCSF Institute for Neurodegenerative Diseases, in a statement. “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 is a severe form of dementia, and individuals with this disease experience memory loss that affects their thinking, behavior and ability to perform everyday tasks. 

According to the Alzheimer’s Association, the disease makes up roughly 60%-80% of all dementia cases worldwide, making it the most common form. While it mostly affects senior citizens, over 200,000 Americans under the age of 65 report having early-onset Alzheimer’s.

There is currently no cure for the disease — the sixth leading cause of death in the U.S. — and current treatment is only able to slow the marching effects. Research has been underway since the discovery of the illness, and scientists now know that, among other things, the protein tau has a large role in the progression of Alzheimer’s. 

The brain is full of neurons that process and transmit information throughout the body, and Alzheimer’s is known to disrupt that process. This is because neurons are supported by structures called microtubules, which keep them healthy by retrieving necessary nutrients, and in turn the microtubules are supported by the tau molecules. 

However, when Alzheimer’s sets in, the tau proteins stop contributing to the microtubules and start to combine, creating tangled threads that disrupt communication between neurons, and ultimately contributes to cell death. 

One question that science had yet to answer was whether all brain cells were affected equally by the tau tangles, which is exactly what the authors of this study sought to investigate.

“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 co-senior author Lea Grinberg, an associate professor in the UCSF Memory and Aging Center

“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,” she added.

The team discovered the particular neurons in question by studying the tissue of 10 donor brains from deceased individuals at different stages of their Alzheimer’s.

Co-authors and doctoral students Kun Leng and Emmi Li then analyzed the tissue through complex single-nucleus RNA sequencing and found two groups of neurons that seemed to be early targets of the disease. 

The first group to start dying sits in the entorhinal cortex, responsible for memory, navigation and perception of time, and further down follows a group from within the superior frontal gyrus, which has to do with one’s self-awareness.

These two groups of neurons had in common the production of the protein RORB, and after studying this trend in tissue from 26 more donor brains at different stages of Alzheimer’s, they confirmed the vulnerability of RORB-expressing neurons. They also found that these neurons attract more tau tangles than other groups.

“These findings support the view that tau buildup is a critical driver of neurodegeneration, but we also know from other data from the Grinberg lab that not every cell that builds up these aggregates is equally susceptible,” said Leng.

Moving forward, Leng plans on using Kampmann lab technology to further investigate why these specific neurons are “selectively vulnerable” and how the RORB protein affects them. The hope is that this lead will allow scientists to learn how to better protect the brain’s weak points against Alzheimer’s.

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

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