Scientists have identified two rare gene mutations that cause the common form of Alzheimer's disease (AD) that strikes after the age of 60.
The two mutations occur in a gene called ADAM10 coding for an enzyme involved in processing the amyloid precursor protein which now becomes the second pathologically-confirmed gene for late-onset AD and the fifthAD gene overall.
Researchers from the Massachusetts General Hospital's MassGeneral Institute for Neurodegenerative Disease (MGH-MIND) found the two mutations in ADAM10 increase generation and accumulation of the toxic amyloid beta (A-beta) protein in the brains of a mouse model of AD.
The mutations also reduce generation of new neural cells in hippocampus, a part of the brain essential to learning and memory.
"This is the first report to document, in animal models, new pathogenic gene mutations for AD since the reports of the original four genes in the 1990s," said Rudolph Tanzi, director of the Genetics and Aging Research Unit at MGH-MIND and senior author of the study.
"What we found regarding the many effects of these two rare mutations in ADAM10 strongly suggests that diminished activity of this enzyme can cause AD, and these findings support ADAM10 as a promising therapeutic target for both
treatment and prevention," Tanzi said.
Researchers conducted experiments using several strains of transgenic mice and found that AD-associated mutations in ADAM10 reduced the release from neurons in the animals' brains of the beneficial protein produced by alpha-secretase
processing of amyloid precursor protein (APP).
Reduced ADAM10 activity caused by the mutations increased the generation of A-beta and its accumulation in plaques, along with producing other AD-associated neurodegenerative signs, researchers found.
Also, reduced ADAM10 activity impaired the generation of new neurons in the hippo campus, one of the areas of the brain most vulnerable to neurodegeneration in AD. The study will be published in the journal Neuron.