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.