Genetic activity analyses show possible therapeutic targets
Findings suggest interactions between genetic, epigenetic changes drive disease
A research team led by scientists at the Massachusetts Institute of Technology (MIT) has completed the most sweeping analysis yet of how genetic activity in brain cells is dysregulated in Alzheimer’s disease.
“What we set out to do was blend together our computational and our biological expertise and take an unbiased look at Alzheimer’s at an unprecedented scale across hundreds of individuals — something that has just never been undertaken before,” Manolis Kellis, PhD, a professor of computer science at MIT’s Computer Science and Artificial Intelligence Laboratory, who co-led the research, said in an institute news release.
The findings, described in four studies published in Cell, suggest complex interactions between genetic and epigenetic changes drive the neurodegenerative disease. Epigenetic modifications refer to the addition of chemical marks to DNA that influence genes’ activities without altering their underlying DNA sequence.
“It’s a multifactorial process,” said Li-Huei Tsai, the director of MIT’s Picower Institute for Learning and Memory, who co-led the studies. “These papers together use different approaches that point to a converging picture of Alzheimer’s disease where the affected neurons have defects in their 3D genome, and that it [causes] a lot of the disease [features] we see.” The genome comprises an organism’s genetic code.
Disease-related changes; gene activity and epigenetics
In the first study, “Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology,” the scientists analyzed the gene expression profiles of 54 types of brain cells. Gene expression refers to the extent that individual genes are “turned on or off.”
The study included brain samples from more than 400 people — 146 without cognitive impairment, 102 with mild cognitive impairment, and 144 with Alzheimer’s-related dementia.
Disease-related expression changes were seen in a range of genes. Many are important for mitochondrial function, the health of the connections between nerve cells, called synapses, the metabolism of fatty molecules, and for maintaining the genome’s structural integrity.
The researchers also identified two subsets of inhibitory neurons that were enriched in the brains of Alzheimer’s patients who showed cognitive resilience, or fewer cognitive problems despite disease-associated molecular features being present. Inhibitory neurons send inhibitory, or suppressive, signals that restrain other neurons’ activity.
“This revelation suggests that specific inhibitory neuron populations might hold the key to maintaining cognitive function even in the presence of Alzheimer’s [features],” said Hansruedi Mathys, PhD, a former postdoctorate at MIT and the study’s first and co-senior author.
In the second study, “Epigenomic dissection of Alzheimer’s disease pinpoints causal variants and reveals epigenome erosion,” scientists analyzed gene expression and epigenetic changes in the brain cells of 29 people with early Alzheimer’s, 15 with late Alzheimer’s, and 48 age-matched healthy people.
Given that all types of cells have the same genome, epigenetic modifications are what determine and maintain cellular identity, causing brain cells to be different from liver cells, for example. Many genes whose expression is impaired in Alzheimer’s also have corresponding changes at the epigenetic level.
Analyzing both gene expression and epigenetic changes “allows us to observe coordinated changes that would otherwise not be detected in isolation,” the researchers wrote.
The findings suggested that, particularly in the later stages of Alzheimer’s, all types of brain cells showed epigenetic erosion, losing many of the epigenetic markers that define their specific cellular identities. This affected some cell types more than others, said the researchers, who noted more research was needed to understand these differences.
Microglia and DNA damage
In “Human microglial state dynamics in Alzheimer’s disease progression,” the researchers analyzed the gene expression and epigenetic profiles of microglia, the brain’s immune cells, from 217 Alzheimer’s patients and 226 people without disease.
“Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood,” wrote the scientists, who identified 12 microglial states based on gene activity and found that, as Alzheimer’s progresses, more microglia progress to inflammatory states that are marked by a higher expression of inflammatory genes. At the same time, fewer microglia enter a state that promotes a balanced, healthy function.
The changes between states were linked to changes in the activity of specific transcription factors, which are proteins that help regulate gene activity. The scientists hope to explore how these proteins might be targeted therapeutically to promote a microglial switch from an inflammatory to a balanced state.
In “Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration,” researchers analyzed patterns of DNA damage in brain samples from 24 people with Alzheimer’s and 23 without.
As more DNA damage accumulated within neurons, the cells’ ability to accurately repair the damage diminished, resulting in abnormal genetic products such as fusions between two different genes and defects in the genome’s three-dimensional structure.
“When you have a lot of DNA damage in neurons, the cells, in their attempt to put the genome back together, make mistakes that cause rearrangements,” said Vishnu Dileep, PhD, a researcher at MIT and one of the study’s co-first authors.
Alongside defects in genome folding, gene fusions mostly affected genes involved in synaptic activity, likely contributing to the cognitive decline of Alzheimer’s.
The findings suggest interventions to help improve neurons’ accurate DNA repair may be a useful for slowing Alzheimer’s, the researchers said.
Kellis and his team plan to use artificial intelligence to identify compounds that might target some genes identified in these studies as potential therapeutic targets. The scientists hope other researchers will use their results to advance Alzheimer’s research and care.
“We want the world to use this data,” Kellis said. “We’ve created online repositories where people can interact with the data, can access it, visualize it, and conduct analyses on the fly.”
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