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November 6, 2024/Neurosciences/Research

Genomic Analysis Finds Connections Between Transposable Elements and Alzheimer's Disease

Understanding TE involvement is a key to developing new treatments

Illustration of a brain

A Cleveland Clinic-led collaboration reveals new connections between DNA transposable elements (TEs) and the development of Alzheimer’s disease in aging brains.

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A study published in Alzheimer’s & Dementia: The Journal of The Alzheimer’s Association is the first to systematically investigate how TEs affect the rest of the human genome in terms of health and disease. Previous preclinical work showed associations between TEs and Alzheimer’s disease, but no comprehensive analyses had been conducted on all TEs to determine which were associated with the condition and how they may contribute to its development.

The new data will inform future Alzheimer’s drug development and research.

Transposable elements

TEs, known colloquially as “jumping genes” or “viral elements,” are pieces of DNA that pop out of the chromosome and insert themselves elsewhere in the genome. This can interrupt genetic coding to create severe mutations that result in dysfunctional or nonfunctional proteins.

About 45% of the human genome is made up of transposable elements, and much of our energy is devoted to preventing them from jumping into other genes. During the aging process and neurodegeneration, fewer resources are devoted to suppressing TEs. Uncontrolled, TEs become dysregulated, and more mutations can occur.

Study details

The study took place in the lab of Feixiong Cheng, PhD, director of Cleveland Clinic’s Genome Center. First author and Cheng Lab postdoctoral fellow Yayan Feng, PhD, analyzed genetic sequencing data from aging brains affected by Alzheimer’s disease from multiple national patient databases funded by the National Institutes on Aging at the National Institutes of Health (NIH).

The team identified widespread TE dysregulation in aging human brains. TEs were inappropriately turned on or off across a variety of genetic backgrounds and disease manifestations. While widespread dysregulation was common across different types of Alzheimer’s disease, the team found specific TEs and risk factors associated with different groups. One example is C1QTNF4 , a key anti-inflammatory gene in Alzheimer’s disease and other neurodegenerative diseases. The team identified a neuron-specific suppressive role of the activated short interspersed nuclear element (SINE) (chr11:47608036-47608220) on expression of C1QTNF4 via reducing neuroinflammation in human iPSC-derived neurons.

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These preliminary findings demonstrated proof-of-concept of TE-regulated neuroinflammation and offers potential anti-inflammatory approaches for targeted therapeutic development for AD.

The researchers validated these findings in the lab using patient-derived brain cells, which suggests that individuals with different genetic backgrounds may benefit from tailored treatments for their disease.

Sex differences

Dr. Cheng says his team’s observations also reveal distinct TE regulation patterns underlying differences in AD pathobiology between male and female brains.

“About 33.8% of differences in TE expression can be explained by sex-specific expression of nearby genes,” he explains. “Those TEs may play roles in sex-specific gene regulatory networks.”

Of note, a LINE-1 transposable element was specifically overexpressed in female neurons. Its nearest gene is FKBP5, which has been implicated in sex-specific cognitive and emotional behavior. While there are no absolutes in biology, the closest gene to a transposable element often regulates or is regulated by that transposable element.

The researchers also highlighted 45 male-biased upregulated TEs from the ROS/MAP brain biobank for endothelial cells and found that a SINE transposable element was significantly upregulated in male endothelial cells. The nearest gene, GFAP, was also upregulated in male AD brains in the ROS/MAP biobank

The master switch

Some DNA sequences act as master switches that change the expression levels of protein-coding genes, and some of these sequences lead to inappropriate TE expression.

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Co-author Xiaoyu Yang, PhD, who directs Functional Genomics Core at the Cleveland Clinic Genome Center, experimentally validated one of these master switches in dish tests on neurons derived from human cells. Artificially suppressing a TE called SINE (short interspersed nuclear element) in these cells activated one regulatory element that in turn activated several anti-inflammatory genes. Mutation of one of the key genes that protects the brain from inflammation is already associated with Alzheimer’s, but the team also identified two additional genes that had not previously been connected.

“By identifying these regulatory elements, our analyses are more comprehensive,” says Dr. Cheng. “We were able to identify far more protein-coding genes and transposable elements whose expression in aging brains are altered during Alzheimer’s disease. These findings will help us identify more potential therapeutic targets to help prevent and treat the disease.”

The team received help interpreting their data from collaborators, including James Leverenz, MD (Director, Luo Ruvo Center for Brain Health); the late Charis Eng, MD, PhD (Genomic Medicine); Andrew Pieper, MD, PhD (Case Western Reserve University, Louis Stokes Cleveland VA Medical Center, Harrington Discovery Institute); and Yin Shen, PhD (University of California, San Francisco).

Even though Dr. Cheng’s team’s analyses focused primarily on Alzheimer’s disease, their overall findings have implications for many other neurogenerative diseases and age-related diseases.

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“Understanding how dysregulation of non-coding genetic elements occurs in aging brains is an important step toward developing therapies that preserve brain function and help us live healthier, happier lives as we get older,” he says.

This research was supported by grants from the National Institute on Aging (NIA).

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