neuronsResearchers have shown that mutations in two proteins associated with familial Alzheimer’s disease disrupt the flow of calcium ions within neurons.

Alzheimer’s disease affects as many as 5 million Americans, 5 percent of whom have the familial form. The hallmark of the disease is the accumulation of tangles and plaques of amyloid beta protein in the brain.

“The amyloid hypothesis has long been invoked to explain the cause of Alzheimer’s” says lead author J. Kevin Foskett, PhD, Professor of Physiology at the University of Pennsylvania School of Medicine.

In the new study, published in the journal Neuron, cells that carried a mutated gene or protein called PS1 showed increased processing of amyloid beta.

This observation links mis-regulation of calcium inside cells with the production of amyloid, a characteristic feature in the brains of people with Alzheimer’s disease.

“The ‘calcium dysregulation’ hypothesis for inherited, early onset familial Alzheimer’s disease has been suggested by previous research findings, but our current study identifies a molecular mechanism that makes this hypothesis very compelling,” says Foskett.

Current therapies for Alzheimer’s include drugs that treat the symptoms of cognitive loss and dementia. Drugs that address the pathology of Alzheimer’s are only experimental.

For example, a vaccine that stimulates antibodies to amyloid beta is currently being investigated. But these new observations suggest that new approaches could be explored.

“The significance of identifying the molecular mechanism and pathway of disrupted calcium signaling is that a number of novel treatment targets can now be developed and tested,” says Foskett.

The central role of calcium signaling disruptions in Alzheimer’s is strengthened by another study in which the Foskett laboratory was involved. This research was published in the June 27 issue of Cell.

“Calcium is the common denominator in our two studies, strongly suggesting that it plays an important role in the development of Alzheimer’s disease,” notes Foskett.

“However, our experiments have identified calcium inside cells as the important feature. No one should consider modifying their dietary intake of calcium as a strategy to limit the risk of developing Alzheimer’s disease, because the body very effectively regulates the amount of calcium absorbed from food and the levels in the blood and brain.

“And it is also very important for people who take calcium channel blockers, for cardiovascular problems for example, not to alter their medication regime as a response to our studies.”

This research was supported by grants from the National Institutes of Health and the Alzheimer’s Disease Core Center at Penn.

Source: University of Pennsylvania