MGH study suggests how amyloid plaques may damage brain cells in Alzheimer's disease

One of the major unanswered questions surrounding Alzheimer's disease – whether and how the amyloid plaques found in the brains of patients with the neurodegenerative disorder actually damage neurons – may be closer to an answer. Using an advanced imaging technique that reveals how brain cells are functioning, researchers from the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) have found that levels of intracellular calcium are significantly elevated in neurons close to plaques in the brains of an Alzheimer's mouse model. The study in the July 31 issue of Neuron also shows 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," says Brian Bacskai, PhD, of MGH-MIND, the study's senior author.

Calcium ions play an essential role in transmitting signals from one neuron to another. Many earlier studies have suggested that alterations in calcium regulation may be involved in the neurodegeneration that characterizes Alzheimer's disease, but the mechanism behind that association has been unclear. The current study was designed to investigate whether it was possible to measure changes in brain function, reflected by alterations in calcium levels, that may be occurring in response to plaque formation. To do so the investigators combined an advanced imaging technique they developed to measure structural changes in the brain – including plaque formation and changes in the physical appearance of neurons – with the use of a fluorescent probe that reports cellular calcium levels, developed by researchers from the Riken Institute in Japan.

After first verifying that their strategy could accurately depict neuronal calcium levels, including specific levels in the projections that carry neuronal signals, the researchers 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.

They then 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 the MGH-MIND team treated plaque-bearing mice with the same calcineurin inhibitor, they 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.

"We need to keep in mind that animal models are not a complete reflection of what happens in human disease, so we can't extrapolate too far down the road," Bacskai says. "But our data do suggest that calcineurin inhibition should be investigated in future studies, which also should look at how amyloid-beta causes calcium overload and whether removing plaques really does improve neuronal health." He also noted that dietary calcium has no effect on the cellular calcium levels examined in this study, so people concerned about the risk of Alzheimer's should not hesitate to take calcium supplements to address other health issues.

Source: Massachusetts General Hospital