Sanford Burnham Prebys Unveils Mysteries Of

image: senior author Jerold Chun, MD, Ph.D., professor and senior vice president of Neuroscience Drug Discovery at Sanford Burnham Prebys.
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Credit: Sanford Burnham Prebys

LA JOLLA, CALIF. – November 15, 2021 – In the first such study, researchers at Sanford Burnham Prebys found molecular changes in the aging brains of people with Down syndrome that could help explain their cognitive challenges, including the uniform development of Alzheimer’s disease in these people later in life. The results, published in the Proceedings of the National Academy of Sciences, could help pave the way for new therapies to help people with Down syndrome and Alzheimer’s disease.

“A surprisingly high level of molecular and cellular diversity has been found affecting unique brain cells, which offers new avenues for understanding both Down syndrome and Alzheimer’s disease,” said lead author Jerold Chun , MD, Ph.D., professor and senior vice president of Neuroscience Drug Discovery at Sanford Burnham Prebys.

An old question requires new techniques
Down syndrome, also known as trisomy 21, occurs when the body has an extra copy of human chromosome 21, resulting in three copies instead of the usual two. Occurring in about one in 700 births, it is the most common chromosomal disease. In addition to their ongoing cognitive challenges, all people with Down syndrome are exceptionally vulnerable to neurodegeneration later in life.

“By the time they reach their forties, every person with Down syndrome will experience Alzheimer’s disease pathology,” Chun explains. “We asked what happens in the brain before Alzheimer’s disease sets in.”

While some of the genes and biochemical pathways involved in the development of Alzheimer’s disease in people with Down syndrome have been identified, the bigger picture – the cellular and molecular changes responsible for triggering these pathways – remains. a mystery.

To study this question, Chun and his team analyzed 29 postmortem brains from Down syndrome using a method called single-core transcriptomics, which examines RNA molecules in individual cells. Since RNA codes for proteins, knowing the RNA sequence reveals which proteins are likely to be produced. And although this technique is widely used in many fields, it has never been used in the brain with Down’s syndrome. Additionally, the article represents the first published use of long read sequencing in the human brain, a more accurate and less error-prone method of gene sequencing.

“Our study revealed unrecognized changes in brain cell types involving hundreds of thousands of unseen RNAs that cannot be seen using standard techniques,” explains Chun. “These can now be taken into account to understand the brain. “

The Down’s Syndrome Brain is a Rich Molecular Landscape
The team discovered several unique aspects of the brain with Down’s syndrome that could help identify the root cause of cognitive challenges with Down’s syndrome and Alzheimer’s disease. First, they found that in Down syndrome there are more inhibitory neurons than excitatory neurons in the brain in general, which means that there are more neurons that block electrical signals from the brain than those that do. trigger them. They also found early and sustained increases in activated microglia, a type of brain cell that is an emerging target for the treatment of common forms of Alzheimer’s disease.

“We could see these microglial characteristics in young brains, long before Alzheimer’s disease happened,” says Chun. “This discovery identifies microglia as an important and early player in the Down syndrome brain.”

The team also found special signatures in thousands of RNAs called intra-exonic junctions, where sections of genetic material encoding proteins come together to form new molecules. These junctions had previously only been observed in a single gene, called APP, the alterations of which are believed to be the cause of Alzheimer’s disease.

The presence of these junctions is consistent with a phenomenon in the brain called somatic gene recombination: when DNA mixes into new combinations of genes. Somatic gene recombination has already been proposed by researchers to operate in Alzheimer’s disease, and these new findings support this hypothesis.

“More studies are needed to confirm whether these new RNAs reflect somatic gene recombination or come from another source,” Chun says. “But given what we’ve already found in Alzheimer’s brain, this new evidence for Down syndrome points in that direction, and we’re excited to study it further.

The best may be yet to come
While the work is far from complete, the research is an unprecedented step forward in examining the neurobiology of Down syndrome across the lifespan, creating new avenues of research.

“It’s wonderful that people with Down syndrome are living longer now than at any time in history, and we hope our research will ultimately help improve their quality of life at all ages,” Chun says. “We are grateful to brain donors, and their families, for helping our team and other researchers continue to shape our understanding of Down syndrome and Alzheimer’s disease.”

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Other authors of the study include Carter R. Palmer, Christine S. Liu, William J. Romanow, and Ming-Hsiang Lee, all of Chun’s lab at the Sanford Burnham Prebys; Palmer and Liu are also students in the Biomedical Sciences program at the University of California at San Diego.

The research was funded by the National Institute on Aging, the National Institute of General Medical Sciences (NIH grants R56AG073965, R01AG065541, R01AG071465, and T32GM007752), the Shaffer Family Foundation, and the Bruce Ford & Anne Smith Bundy Foundation.

About the Sanford Burnham Prebys Medical Discovery Institute
Sanford Burnham Prebys is a preeminent and independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discovery for profound impact on human health. For over 40 years, our research has produced breakthroughs in cancer, neuroscience, immunology and childhood illnesses, and is anchored in our NCI Designated Cancer Center and advanced drug discovery capabilities. . For more information, visit us on SBPdiscovery.org or on Facebook facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.


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