How amyloid plaques damage brain cells in Alzheimer's

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Washington, July 31 : Researchers have unravelled one of the biggest mysteries related to Alzheimer's disease- how amyloid plaques associated with the neurodegenerative disorder can actually damage neurons.

Making use of an advanced imaging technique, researchers at the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) found that levels of intracellular calcium are significantly elevated in neurons close to plaques in the brains of an Alzheimer's mouse model.

They also demonstrated how this calcium overload can interfere with the transmission of neuronal signals and activate a pathway leading to further cell damage.

"While a connection between calcium regulation and Alzheimer's pathology has been predicted for many years, this is the first direct observation of a connection between amyloid plaques, calcium accumulation and a neurodegenerative mechanism in the most relevant animal model," said Brian Bacskai, PhD, of MGH-MIND, the study's senior author.

Calcium ions have a vital role to play in transmitting signals from one neuron to another. This study was designed to find out if it was possible to measure changes in brain function, reflected by alterations in calcium levels that may be occurring in response to plaque formation.

The researchers combined an advanced imaging technique they developed to measure structural changes in the brain, with the use of a fluorescent probe that reports cellular calcium levels.

They then showed that dendrites, which receive nerve signals, were almost six times more likely to have excessive levels of calcium in transgenic mice with amyloid plaques than in normal mice. Those excess calcium levels were even higher - nearly doubling - in neurons adjacent to plaques. Later, they found how this calcium overload probably interferes with neuronal communication.

Normally specific signals being transmitted are reflected by distinct calcium levels in structures called dendritic spines, but in mice with the plaque-associated elevations, calcium levels were the same throughout a dendrite instead of changing at the locations of the spines. Those dendrites in which calcium levels were highest also had structural changes similar to those seen in the brains of patients who have died with Alzheimer's disease.

Cellular calcium overload can damage cells through a pathway involving the action of an enzyme called calcineurin, and a previous study found that treatment with a calcineurin inhibitor appeared to improve cognition in an Alzheimer's mouse model.

After treating plaque-bearing mice with the same calcineurin inhibitor, the researchers found that neuronal calcium levels were partially moderated and dendrites did not continue to degenerate, indicating that the calcineurin pathway may be a potential therapeutic target.

The study is published in the latest issue of Neuron.

ANI

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