Mosaicism adds more amyloid precursor than in normal brains. Mosaicism is a condition in which cells within the same person have a different genetic makeup. This condition can affect any type of cell, including: Blood cells. Egg and sperm cells (gametes).

Alzheimer’s patients have brains with significantly more genetic variation than brains of those without the disease, according to a study led by scientists at The Scripps Research Institute.

The finding may help scientists track down the mechanism that causes nearly all cases of Alzheimer’s, a mechanism that is not well understood. And with a better understanding of the mechanism, an effective therapy for Alzheimer’s might be developed. Currently, no effective therapy for the neurodegenerative disease exists.

Scientists led by TSRI professor Jerold Chun found that neurons in brains of Alzheimer’s patients had significantly more copies of chromosome 21 fragments, but not more whole chromosomes. The fragments carry the gene APP, or amyloid precursor protein, which has been liked to Alzheimer’s. Moreover, those with Down Syndrome carry three copies of chromosome 21 throughout their body, and those with Down Syndrome tend to develop Alzheimer’s as they age.

The Alzheimer’s cells contain on average about 200 million extra base pairs, Chun said by email Wednesday. The researchers don’t know where that extra DNA is from.

Variations within the genetic makeup of a single organism is called genetic mosaicism. Its presence in people has only been appreciated in recent years. The traditional assumption has been that the great majority of cells in humans are genetically identical.

The study was published Wednesday in the journal eLife. It examined post-mortem brains of 32 Alzheimer’s brains and 21 non-Alzheimer’s brains.

“Our findings open a new window into the normal and diseased brain by providing the first evidence that DNA variation in individual neurons could be related to brain function and Alzheimer’s disease,” said Jerold Chun, the study’s senior author, in a Scripps Research press release. Chun is a professor at TSRI and at the institute’s Dorris Neuroscience Center. Diane M Bushman and Gwendolyn E Kaeser are the study’s co-first authors.

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The laboratory of Professor Jerold Chun, center, includes (left to right) Yun Yung, Richard Rivera, Benjamin Siddoway and Gwendolyn Kaeser. Not pictured: Diane M. Bushman. — The Scripps Research Institute
A very small percentage of Alzheimer’s cases are known to be caused by a genetic mutation that increases deposits of tangled protein plaques called amyloid beta. There is considerable evidence that these and another protein called tau damage the brain, leading to the loss of memory and other symptoms of Alzheimer’s as brain cells are damaged and destroyed.

However, more than 95 percent of Alzheimer’s can’t be tied to a specific gene or a family history of the disease. These cases are called “sporadic” Alzheimer’s, and they were the focus of the study.

Scientists who examined the study said it represented a great advance in the field.

The study will be considered “a major breakthrough” in understanding sporadic Alzheimer’s, and it opens new avenues for research, said Dr. Michael Rafii, director of the Memory Disorders Clinic and assistant professor of neurosciences at UC San Diego.

“It also further explains the observed link between Down syndrome and AD,” Rafii said by email. “One interesting question that comes out of this work is what specific environmental factors may be causing the genomic mosaicism that leads to increased APP copy number and subsequent amyloid plaque formation, neurodegeneration and dementia.”

Source : UCTSanDiego