Why memory-forming neurons are vulnerable to Alzheimer’s disease

When Alzheimer’s disease develops, the entire brain does not collapse immediately. Instead, it begins with a distinct deterioration of a group of brain cells in the entorhinal cortex, and the mind is elucidated like a strict clockwork. These so-called fragile neurons are responsible for shuttled experience to memory. They always go first.

Understanding why patients lose these vulnerable neurons prematurely may be key to discovering new treatments for Alzheimer’s disease. Now, new research describes the molecular factors that shed light on the inner workings of this subset of neurons, which makes the entorhinal brain cells uniquely sensitive to degeneration.

“Understanding the specificities of the brain’s most vulnerable neurons could potentially open new avenues of treatment,” said senior researcher Jean-Pierre Roussarie. Of the late Paul Greenguard Institute for Molecular and Neuronal Sciences that announced the discovery To Neuron..

“Brain ball”

So far, most attempts to develop treatments for Alzheimer’s disease have failed. However, most efforts made have focused on the accumulation of Aβ peptides that form plaques throughout the brain. These plaques are the first signs of Alzheimer’s disease and are the most studied.

The second manifestation of the disease is less celebrated, but there are more possibilities. After the formation of the first amyloid plaques in the brain, a cluster of tau proteins known as neurofibrillary tangles clog the interior of neurons. Unlike amyloid plaques, this latter aggregate of proteins is initially clustered only within different groups of cells in the entorhinal cortex. The pure predictability of the process makes it an attractive therapeutic target.

But to date, scientists know little about the nuances of tickling and entanglement vulnerable neurons. With that in mind, researchers sought to catalog the genetic factors that make olfactory endothelial cells uniquely vulnerable to neurofibrillary tangles.

“Tests have taken place one after another, and accumulated a great deal of knowledge about the mechanisms that produce amyloid plaques,” Rusally says. “But what’s happening downstream of amyloid accumulation, and how these plaques induce neurofibrillary tangles in vulnerable neurons, is a far more puzzle. New therapeutic targets Is a place where you can discover.”

The biggest obstacle to studying these brain cells has been the lack of an easy way to distinguish vulnerable neurons from their neighbors. For Lucary and his colleagues, BacTRAP has given the answer. The bacTRAP technology, developed at Rockefeller by Greengard and Nathaniel Heintz, makes it possible to catalog proteins within specific populations of mouse neurons.

“We needed something like a microdissection of these neurons from a complex and overcrowded brain bowl,” he says. Mark Frajolet, Laboratory director and co-author of research.

BacTRAP allowed researchers to isolate vulnerable neurons and analyze how they were genetically different from the more elastic brain cells. A team at Princeton University, headed by Olga Troyanskaya, designed computer algorithms to allow the team to focus only on the genetic abnormalities most likely to be associated with neurodegeneration.

“The goal was to form the big picture, not the list of genes,” Flajolet says. “Only with these sophisticated data analysis frameworks can we reach the bottom of something as complex as the neurodegenerative cascade of Alzheimer’s disease.”

From neurofibrillary tangles to therapeutic targets

The findings highlight a set of genes that are likely involved in making the entorhinal cortical neurons an easy target for degeneration.

The most compelling of them are thought to play a major role in the early stages of Alzheimer’s disease-first determining whether tau protein aggregates into neurofibrillary tangles. This gene produces a protein called PTBP1. It is a so-called splice factor that directs cells to make one of two subtypes of tau protein. Previous studies have shown that the characteristic protein clumps of Alzheimer’s disease occur specifically when the ratio of these two flavors of tau is disturbed-new findings show tau variant levels. Suggests that cells that are disturbed may cause the disease.

“There was a lot of excitement when Tau jumped out,” says Vicky Yao, assistant professor and co-author of computer science at Rice University. Neuron To report. “Obtaining the causes of increased vulnerability to neurons can lead to multiple ways to reduce vulnerability.”

Successful strategies for preventing and treating neurodegeneration will likely include a variety of approaches, Roussarie adds. For example, future drugs may need to target plaque preparations or neurofibrillary tangles. The first step to prevent the latter is to understand why some neurons tend to get tangled from the beginning.

“Neuron diversity has never been considered before,” says Roussarie. “Many people are studying neurofibrillary tangles, but so far they have begun to address it through the prism of neuronal vulnerability.”