Mechanism explains calcium abnormalities in Alzheimer's brain

June 25, 2008

A new study uncovers a mechanism that directly links mutations that cause early onset Alzheimer's disease (AD) with aberrant calcium signaling. The research, published by Cell Press in the June 26th issue of the journal Neuron, provides exciting molecular insights into the pathology of AD and may lead to new treatment strategies.

AD is a devastating neurodegenerative disease that affects early 18 million people in the world. Most cases of AD occur spontaneously after the age of 60 but about 10% of cases are inherited and can develop decades earlier. Early onset familial AD (FAD) is caused by mutated amyloid precursor protein, which can lead to aggregation of sticky clumps of amyloid beta protein in the brain, and mutated presenilins (PS), enzymes which have been implicated in amyloid processing.

Recent research has also linked mutant PS expression with exaggerated intracellular calcium release in several model systems, including cells from FAD patients. "Accumulating evidence suggests that sustained disruption of intracellular calcium signaling may play an early role in AD pathogenesis," says study author Dr. J. Kevin Foskett from the University of Pennsylvania. Calcium plays a central role in many aspects of brain physiology including growth, plasticity and learning and memory as well as cell death and degeneration.

Dr. Foskett and colleagues found that biochemical interactions of FAD mutant PS with an intracellular calcium release channel, called inositol trisphosphate receptor (InsP3R), profoundly increased channel activity in a manner that could account for exaggerated calcium responses in cells exposed to normal stimulation and caused low level calcium signaling in unstimulated cells. The researchers went on to show that this enhancement of channel activity was directly involved in mutant PS-mediated amyloid beta generation, a hallmark of AD.

"We have discovered a mechanism that can account for altered calcium signaling in AD cells that involves a biochemical and functional interaction of FAD mutant PS with the InsP3R calcium release channel. These observations provide unique molecular insights into the calcium dysregulation hypothesis of AD pathogenesis and they suggest novel targets for therapeutic intervention," concludes Dr. Foskett.

In a related finding, published in the June 27th issue of the journal Cell, abnormal calcium signaling was also linked to the more common spontaneously occurring form of AD. In this study, Dr. Fabien Campagne from Weill Medical College, Dr. Philippe Marambaud from Albert Einstein College of Medicine and their colleagues discovered a mutation associated with late onset, sporadic AD that disrupted a previously uncharacterized brain calcium channel and led to subsequent accumulation of amyloid beta protein. Therefore, dysregulation of intracellular calcium levels appears to play a role in both sporadic and hereditary AD.

Source: Cell Press

Explore further: Study shows Alzheimer's disease-related peptides form toxic calcium channels in the plasma membrane

Related Stories

Rescuing fruit flies from Alzheimer's disease

July 15, 2010

Investigators have found that fruit fly (Drosophila melanogaster) males -- in which the activity of an Alzheimer's disease protein is reduced by 50 percent -- show impairments in learning and memory as they age. What's more, ...

Calcium may be the key to understanding Alzheimer's disease

July 18, 2008

Researchers at the University of Pennsylvania School of Medicine 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 ...

Recommended for you

How the finch changes its tune

August 3, 2015

Like top musicians, songbirds train from a young age to weed out errors and trim variability from their songs, ultimately becoming consistent and reliable performers. But as with human musicians, even the best are not machines. ...

Machine Translates Thoughts into Speech in Real Time

December 21, 2009

(PhysOrg.com) -- By implanting an electrode into the brain of a person with locked-in syndrome, scientists have demonstrated how to wirelessly transmit neural signals to a speech synthesizer. The "thought-to-speech" process ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.