Plasticity can make neurons vulnerable to Alzheimer’s disease

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Neurons that regularly remodel are more prone to Alzheimer’s disease and die when that remodeling goes wrong, a new study suggests. The work is the first to track the progression of Alzheimer’s disease at the genetic and molecular level within neurons vulnerable to the disease.

“Identifying the molecular characteristics of neurons that are especially vulnerable to neurodegeneration is important both for a basic understanding of Alzheimer’s disease and for the future development of better diagnostic and treatment options,” says study co-author Olga Troyanskaya, deputy director of genomics at the Flatiron Institute. Computational Biology Center in New York City and Professor at Princeton University.

Using a machine learning framework that integrated experiments with neuron type-specific mice with human studies, the researchers compared two types of Alzheimer-susceptible neurons with five resistant types. The most significant difference was that vulnerable neurons were enriched with processes related to the remodeling of connections with adjacent neurons.

The findings suggest that aging and the buildup of a protein fragment called amyloid-beta can cause the remodeling process to go crazy, creating tangles of tau proteins that lead to the death of neurons. The work is the first to link beta amyloid and tau proteins, two main suspects previously proposed in Alzheimer’s progression, at the genetic and molecular level.

“By understanding what makes these neurons more vulnerable, we can understand what causes Alzheimer’s to start killing neurons,” says study co-author Vicky Yao, an assistant professor of computer science at Rice University in Houston, who The project started while working in the Troyanskaya group. at Princeton “The question now is whether we can somehow make these neurons more resistant.”

Yao led the work with Jean-Pierre Roussarie, a senior research associate at the Fisher Center for Alzheimer’s Disease Research at Rockefeller University in New York City. The researchers present their findings on June 29 at Neuron.

Alzheimer’s is a progressive disorder that causes brain cells to burn out and die. The disease first targets memory and navigation-related neurons. Over time, the disease spreads to other neurons. In the United States, Alzheimer’s is the sixth leading cause of death and the fifth leading cause of death for Americans over the age of 65.

The cause of the disease remains unclear. Previous studies have identified genes that increase Alzheimer’s risk, but scientists still don’t know why the disease begins to attack neurons. A challenge in studying the disease is that the brain begins to deteriorate rapidly after death, distorting any possible postmortem findings.

For the new study, Roussarie and colleagues generated custom mouse gene lines to study neurons. Each line targets a single type of neuron, with genetic changes to make gene transcription in those neurons easier to track (including adding a green fluorescent protein). The researchers developed mouse lines targeting Alzheimer’s-resistant neurons and others targeting neurons vulnerable to the disease.

In the new article, the researchers show that human and mouse neurons were nearly identical at the molecular level, making rodents excellent substitutes for studying Alzheimer’s.

The researchers combined experimental data from Roussarie’s mice with Yao’s human genetic computational models, which show when and where genes related to Alzheimer’s-related processes are expressed in the brain and how those genes interact with other genes. Together, the two data sources produced a profile of the characteristics that make neurons vulnerable to Alzheimer’s.

The profile showed two of the usual suspects in Alzheimer’s disease: beta-amyloid and tau. Beta amyloid is a fragment of protein that can aggregate, forming plaques that fill the spaces between nerve cells. Tau proteins, the main candidate in the profile, stabilize microtubules, molecular bars that shape neurons and form the backbone of connections between neighboring neurons. When tau proteins are misfolded, they can create tangled threads that block a neuron’s transport system, preventing neurons from working properly.

“When I made the predictions the first time, I actually went back and double-checked because I thought this was too good to be true,” says Yao. “These were things that we already knew were related to Alzheimer’s, and we were able to link them together. It was a verification that we were on the right track.”

Scientists have long debated which process, involving beta amyloid or tau, is responsible for the onset of Alzheimer’s disease, but the new findings suggest that the two are connected. The work strongly linked PTB, a gene that regulates the formation of various flavors of the tau protein, with Alzheimer’s disease. If PTB is deregulated, the proportion of tau protein is discarded. This imbalance causes the tau proteins to begin to aggregate, forming the tangled threads. The researchers propose that age and beta amyloid accumulation increase the risk of this dysregulation.

The researchers plan to continue their research looking for other characteristics that make neurons vulnerable to disease. Gathering more information about the onset of Alzheimer’s disease will help develop possible treatments that prevent the disease from taking hold in the first place, Yao says.

Provided by the Simons Foundation