Calcium may be the key to understanding Alzheimer's

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Washington, July 19 : A new study by researchers at the University of Pennsylvania School of Medicine has cited that calcium may hold the key to understanding Alzheimer's disease.

Researchers have shown that mutations in two proteins associated with familial Alzheimer's disease disrupt the flow of calcium ions within neurons. The two proteins, called PS1 and PS2 (presenilin 1 and 2), interact with a calcium release channel in an intracellular cell compartment.

"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," said lead author J. Kevin Foskett, PhD, Professor of Physiology.

He added: "Mutated PS1 and PS2 caused exaggerated cellular calcium signalling in cells through a calcium channel in the endoplasmic reticulum called the inositol trisphosphate receptor [InsP3R], suggesting that it or other proteins in this calcium signalling pathway could be targets for new Alzheimer's disease therapies."

Alzheimer's disease is characterised by 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," said Foskett.

In the new study, cells that carried the disease-causing mutated form of PS1 showed increased processing of amyloid beta that depended on the interaction of the PS proteins with the InsP3R. This suggests a link between mis-regulation of calcium inside cells with the production of amyloid, a characteristic feature in the brains of people with Alzheimer's disease.

Currently Alzheimer's is treated by drugs that take care of the symptoms of cognitive loss and dementia. Drugs that address the pathology of Alzheimer's are only experimental.

The researchers are now hoping to find out if other mutations in PS1 and PS2 that cause Alzheimer's disease have a similar effect on calcium signalling in the brain, and to identify drugs that might inhibit the interaction between InsP3R and PS1 or PS2 specifically in the brain.

"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," said Foskett.

The vital role of calcium signaling disruptions in Alzheimer's is supported by another study which involved the Foskett laboratory. In this study investigators discovered a new gene that influences calcium regulation and amyloid beta levels in the brain.

"Calcium is the common denominator in our two studies, strongly suggesting that it plays an important role in the development of Alzheimer's disease. 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," noted Foskett.

The study appeared in the upcoming issue of Neuron.

ANI

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