A New Piece of the Alzheimer’s Puzzle

Posted on October 16th, 2018 by Dr. Francis Collins

For the past few decades, researchers have been busy uncovering genetic variants associated with an increased risk of Alzheimer’s disease (AD) [1]. But there’s still a lot to learn about the many biological mechanisms that underlie this devastating neurological condition that affects as many as 5 million Americans [2].

As an example, an NIH-funded research team recently found that AD susceptibility may hinge not only upon which gene variants are present in a person’s DNA, but also how RNA messages encoded by the affected genes are altered to produce proteins [3]. After studying brain tissue from more than 450 deceased older people, the researchers found that samples from those with AD contained many more unusual RNA messages than those without AD.

The unusual messages apparently arose from changes in a normal process called RNA splicing. The flow of molecular information (otherwise known as the central dogma of molecular biology) goes from DNA to RNA to protein, but there are some important additional details. Forty years ago, we learned that the DNA instructions to make a human protein are often interrupted by “introns.” These introns are spacer sequences that are transcribed into RNA, but then must be spliced out before the mature messenger RNA is “ready for its close up” to be translated into protein by the ribosome.

RNA splicing doesn’t always happen in exactly the same way, depending on which introns are removed and which signals are used to direct the removal. When a particular RNA has multiple possible outcomes, it is called “alternative splicing.”

Though alternative RNA splicing is common throughout the body, it occurs at especially high frequency in the nervous system, including the brain [4]. Several years ago, researchers got their first hints that there may be altered splicing in AD and other forms of dementia [5].

In the new study, researchers led by Towfique Raj, Icahn School of Medicine at Mount Sinai, New York, and Philip De Jager, Columbia University, New York, wanted to take a more detailed look. Their goal was to generate a first comprehensive genome-wide map of splicing variation involving the prefrontal cortex. That’s the part of the brain involved in “executive functions,” such as planning and setting goals.

To begin, the team sequenced RNA from the prefrontal cortex of deceased participants in two NIH-funded studies of the aging process: the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). The older participants enrolled in both studies decades ago without any known dementia. But, over the years, many had cognitive decline. Indeed, after their death, autopsies found that 60 percent had plaques and tangles in their brains that were consistent with an AD diagnosis.

A sophisticated analysis of the RNA sequence data from these participants revealed altered RNA splicing associated with AD that corresponded to 84 genes. As confirmation, many of those same changes also turned up in an independent sample of brain tissues from patients with AD in the Mount Sinai NIH Brain and Tissue Repository.

For three of these genes, the new findings help to explain how known genetic variants associated with an increased Alzheimer’s risk exert their effects in the brain. Others offer brand new leads. Importantly, specific genes were frequently affected in specific ways, an indication that the unusual splicing events didn’t owe to general problems in processing the RNA.

It’s worth noting that this list of genes points to an important role for certain cellular pathways in breaking down and clearing away unneeded or toxic proteins. While much more work is needed, it’s now clear that changes in RNA splicing are a key contributor to the functional deficits in the AD brain.

Ultimately, the new findings may have significant implications for treatment and diagnosis. For instance, RNA-targeted biomarkers might hold potential for picking up on early signs of AD in the cerebrospinal fluid. An emerging class of drug compounds based on small snippets of DNA, or oligonucleotides—which is already showing great promise in treating spinal muscular atrophy and other conditions—might target aberrant RNAs in the AD brain, offering new avenues for treatment.

These new findings will now serve as a reference map for the aging brain, with potential to elucidate many neurologic and psychiatric diseases. This valuable information should help enable progress in a critically important scientific journey.

References:

[1] Field Synopsis of Genetic Association Studies in AD, Alzforum.org

[2] Alzheimer’s Disease Fact Sheet, Yesterday, Today & Tomorrow: NIH Research Timelines.

[3] Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer’s disease susceptibility. Raj T, Li YI, Wong G, Humphrey J, Wang M, Ramdhani S, Wang YC, Ng B, Gupta I, Haroutunian V, Schadt EE, Young-Pearse T, Mostafavi S, Zhang B, Sklar P, Bennett DA, De Jager PL. Nat Genet. 2018 Oct 8. [Epub ahead of print]

[4] Alternative Splicing in Neurogenesis and Brain Development. Su CH, D D, Tarn WY. Front Mol Biosci. 2018 Feb 12;5:12.

[5] U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer’s disease. Bai B, Hales CM, Chen PC, Willcock DM, Levey A, Lah JJ, Peng J, et al. Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16562-16567.

Links:

Alzheimer’s Disease & Related Dementias (National Institute on Aging/NIH)

Religious Orders Study (Rush University, Chicago)

Rush Memory and Aging Project (Rush University, Chicago)

Mount Sinai/JJ Peters VA Medical Center NIH Brain and Tissue Repository (Icahn School of Medicine at Mount Sinai, New York)

Raj Lab (Icahn School of Medicine at Mount Sinai, New York)

Philip De Jager (Columbia University, New York)

NIH Support: National Institute of Mental Health; National Institute on Aging