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Alzheimer's: What leads to brain cell damage?

Scientists have uncovered a mechanism through which a toxic brain protein that is a hallmark of Alzheimer's disease can damage neurons, or brain cells.


By Catharine Paddock PhD, Medical News Today

The team at the Grenoble Institute of Neurosciences in France that made the discovery also suggests a potential way to disarm the mechanism during the early stages of the disease.

The study concerns the functioning of dendritic spines, which are the tiny structures in the branching parts of brain cells that receive signals from other brain cells.

It appears that beta-amyloid, a toxic protein that builds up in the brains of people with Alzheimer's disease, triggers a mechanism that disrupts the functioning of dendritic spines.

The mechanism disables a protein called cofilin 1, and the activity of this protein is crucial for the healthy functioning of dendritic spines.

The Journal of Neuroscience has recently published a study paper on the research.

It describes how the team used brain tissue samples from mouse models and people with Alzheimer's disease to arrive at their findings.

A key finding was that exposure to beta-amyloid peptides, which are the building blocks of the toxic protein, led to an increase in the inactive form of cofilin 1.

"What is more," notes study co-author José Martínez-Hernández, Ph.D., who now works in the Department of Biochemistry and Molecular Biology at the University of the Basque Country in Spain, "the beta-amyloid peptides lead to fewer spines in the long term; when they cease to be functional, they are gradually lost over time."


Alzheimer's disease destroys brain connections

Alzheimer's is an irreversible brain disease that gets worse over time. It is the most common cause of dementia.

The disease erodes the ability to remember, think, and perform simple tasks, until people with Alzheimer's can no longer care for themselves. Most individuals begin to experience symptoms in their mid-60s.

According to the National Institute on Aging, experts believe that there are more than 5.5 million people living with Alzheimer's disease in the United States.

Different forms of dementia have different hallmarks. In Alzheimer's disease, the distinguishing features include a toxic buildup of beta-amyloid and another protein called tau and the loss of connections between neurons.

Neurons transmit information in the brain and carry signals from the brain to other parts of the body, such as organs and muscles.

The billions of neurons in the brain communicate with each other by sending and receiving chemical messages across "specialized structures" known as synapses. These structures come and go and strengthen and weaken, depending on experience.

The brain stores long-term information by changing the chemistry and structure of synapses. Scientists believe that the dynamic, fluctuating nature of synapses underpins memory and learning.


Synapses, dendritic spines, and cytoskeletons

When information, in the form of chemical messengers, travels across a synapse from one brain cell to another, branching structures called dendrites bring the signals into the receiving neuron.

Dendritic spines are tiny protrusions on the branching structures that actively receive signals from other brain cells.

The recent research reveals how, in brain tissue affected by Alzheimer's disease, toxic beta-amyloid impairs synapses by reducing the activity of cofilin 1 protein in dendritic spines.

Brain cells have a cytoskeleton that not only upholds their three-dimensional structure but is also responsible for the dynamic transport of substances inside the cell.

Cytoskeletons have this ability because they consist of highly active actin filaments, which, as Martínez explains, "are anchored but are constantly moving as if they were an escalator."

Cofilin 1 breaks the filaments into separate actin units, "a task that keeps the dynamics active," he adds.


Inactivating cofilin 1 impairs dendritic spines

Phosphorylation, or the addition of a phosphoryl group, to cofilin 1, however, renders the protein inactive.

The researchers observed how exposure to beta-amyloid peptides in cultured brain cells led to more phosphorylated cofilin 1. This reduced the dynamism of actin filaments and, in turn, impaired the ability of dendritic spines to receive signals.

Further investigation revealed that an enzyme called Rho-associated protein kinase (ROCK) could be a target for reducing cofilin 1 phosphorylation. The enzyme activates and deactivates other molecules through phosphorylation.

Tests with a drug called Fasudil that blocks ROCK showed that it reversed the effects that the team observed in the actin filaments.

Martínez says that the study findings support the notion that targeting ROCK and cofilin 1 during the early stages of Alzheimer's disease might potentially avert the damage that beta-amyloid inflicts on dendritic spines and synapses.

He suggests that further research into drugs that "specifically stop that phosphorylation" of cofilin 1 in brain cells could be a promising avenue for finding new Alzheimer's disease treatments.

"We have not come up with an action mechanism, but we confirmed that the inhibition of the phosphorylation pathway of cofilin 1 prevents exposure to beta-amyloid peptides from causing the deactivation of the protein and the consequent effect on the cytoskeleton of the dendritic spines."
- José Martínez-Hernández, Ph.D.
Alzheimers: Mental health tips

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