TSRI scientists find more DNA and extra copies of disease gene in Alzheimer's brain cells

Feb. 6, 2015

Scientists at The Scripps Research Institute (TSRI) have found diverse genomic changes in single neurons from the brains of Alzheimer’s patients, pointing to an unexpected factor that may underpin the most common form of the disease. A new study, published in the online journal eLife, shows that Alzheimer’s brains commonly have many neurons with significantly more DNA and genomic copies of the Alzheimer’s-linked gene, APP, than normal brains.

Researchers have long known about disease-related protein accumulations, called amyloid plaques, in the brains of Alzheimer’s patients. They’ve also known that chromosome 21 plays a role in the disease, due to Alzheimer’s-like symptoms in people with Down syndrome (with three copies of chromosome 21). This chromosome contains the APP gene, which can lead to production of the primary component of the damaging amyloid plaques.

Jerold Chun, PhD, the study’s senior author, and his laboratory group have had a longstanding interest in genomic variation among brain cells, which produces “genomic mosaicism.” In 2001, Chun was the first to report that the brain contains many distinct genomes within its cells—much like the colorful tiles in an artist’s mosaic.

In the new study, Chun and his colleagues first analyzed the overall DNA content in cells, comparing 32 post-mortem Alzheimer’s brains and 21 post-mortem non-diseased brains. Remarkably, the researchers found that more than 90 percent of sporadic Alzheimer’s disease brains displayed highly significant DNA increases of hundreds of millions more DNA base-pairs, compared with control samples, showing that genomic mosaicism was altered in the Alzheimer’s brain. Interestingly, these changes were not found everywhere, but were greatest in a part of the brain involved with complex thought.

Next, the researchers used single-cell qPCR to determine the numbers of APP copies in 154 individual neurons from Alzheimer’s and normal brains. They also tested the neurons using a technique called FISH as an independent method to assess APP copies using fluorescent probes. They then quantified the copies of APP using both techniques.

The tests showed that neurons from patients with sporadic Alzheimer’s disease were four times as likely to contain more than the normal two copies of APP, with some Alzheimer’s neurons containing up to 12 copies.

Read more at the TSRI website