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Many individuals associate Alzheimer’s disease with its alarming signs like memory impairment, while innovative medications focus on pathological facets of disease symptoms, such as amyloid protein plaques. Now, an extensive new open-access investigation in the Sept. 4 issue of Cell by researchers at MIT underscores the significance of comprehending the illness as a struggle over how effectively brain cells manage the expression of their genes. The research delineates a detailed depiction of a critical effort to sustain proper gene expression and regulation, where the outcomes of success or failure are nothing short of the preservation or loss of cell functionality and cognition.
The research introduces a pioneering, multimodal atlas of integrated gene expression and regulation encompassing 3.5 million cells across six brain areas, acquired by profiling 384 post-mortem brain specimens from 111 donors. The team examined both the “transcriptome,” which illustrates which genes are translated into RNA, and the “epigenome,” the ensemble of chromosomal modifications that dictate which sections of DNA are accessible and, consequently, utilized among various cell types.
The resulting atlas unveiled numerous insights indicating that the advancement of Alzheimer’s is marked by two primary epigenomic trends. The first is that at-risk cells in crucial brain areas undergo a collapse of the meticulous nuclear “compartments” they typically uphold to ensure certain segments of the genome are open for expression while others remain secured. The second key discovery is that at-risk cells face a reduction in “epigenomic information,” implying they lose their connection to the distinct pattern of gene regulation and expression that provides them with their particular identity and facilitates their healthy operation.
Accompanying the findings of compromised compartmentalization and the degradation of epigenomic information are numerous specific observations identifying molecular circuits that disintegrate by cell type, region, and gene network. For example, the researchers found that when epigenomic conditions worsen, it facilitates the expression of multiple genes associated with the disease, whereas if cells succeed in maintaining their epigenomic order, they can manage disease-related genes effectively. Additionally, the researchers noticed a clear correlation: as epigenomic breakdown occurred, individuals lost cognitive abilities, whereas with maintained epigenomic stability, cognition persisted.
“To grasp the circuitry and logic behind gene expression alterations in Alzheimer’s disease [AD], it was essential to understand the regulation and upstream control of all modifications transpiring, and that’s where the epigenome plays a role,” states senior author Manolis Kellis, a professor at the Computer Science and Artificial Intelligence Lab and leader of MIT’s Computational Biology Group. “This constitutes the first extensive, single-cell, multi-region gene-regulatory atlas of AD, systematically analyzing the dynamics of epigenomic and transcriptomic processes throughout disease advancement and resilience.”
By offering that thorough examination of the epigenomic mechanisms involved in Alzheimer’s progression, the study delivers a template for developing new Alzheimer’s therapies that can address factors underpinning the widespread degradation of epigenomic control or the specific manifestations impacting critical cell types, such as neurons and supporting glial cells.
“The foundation for innovating new and more effective treatments for Alzheimer’s disease rests on enhancing our understanding of the mechanisms that lead to the breakdown of cellular and network functionality in the brain,” asserts Picower Professor and co-corresponding author Li-Huei Tsai, director of The Picower Institute for Learning and Memory and one of the founding members of MIT’s Aging Brain Initiative, alongside Kellis. “This fresh data enhances our comprehension of how epigenomic factors spur disease.”
Members of Kellis Lab, Zunpeng Liu and Shanshan Zhang, serve as the study’s co-lead authors.
Compromised compartments and diminished information
Among the post-mortem brain samples examined in this research, 57 were sourced from donors participated in the Religious Orders Study or the Rush Memory and Aging Project (collectively termed “ROSMAP”) who exhibited neither AD pathology nor symptoms, while 33 were from donors exhibiting early-stage pathology and 21 from those at a late stage. Consequently, these samples provided abundant insights into the symptoms and pathology experienced by each donor prior to their demise.
In the recent study, Liu and Zhang merged analyses of single-cell RNA sequencing of the samples, which identifies the genes being expressed in each cell, and ATACseq, which assesses the accessibility of chromosomal regions for gene expression. Taken collectively, these transcriptomic and epigenomic measurements enabled the researchers to unravel the molecular intricacies of how gene expression is governed across seven broad categories of brain cells (e.g., neurons or other glial cell varieties) and 67 subtypes of cell types (e.g., 17 varieties of excitatory neurons or six forms of inhibitory ones).
The researchers cataloged over 1 million gene-regulatory control regions that different cells utilize to define their distinct identities and functionalities through epigenomic marking. Furthermore, by contrasting the cells from Alzheimer’s-affected brains with those unaffected, while considering the stage of pathology and cognitive symptoms, they were able to establish robust associations between the degradation of these epigenomic markings and, ultimately, the loss of function.
For instance, they observed that among individuals who progressed to late-stage AD, compartments that typically repress expression began to open up, while compartments that were generally more accessible during health became increasingly restrictive. Alarmingly, when the normally repressive compartments of brain cells opened, they were found to be more affected by disease.
“For Alzheimer’s patients, compartments that usually repress expression opened up, leading to increased gene expression levels, which correlated with diminished cognitive function,” clarifies Liu.
However, when cells successfully maintained their compartments in order and expressed the genes they were designed to, individuals sustained cognitive integrity.
Meanwhile, based on the cells’ expression of regulatory elements, the researchers devised an epigenomic information score for each cell. In general, the level of information declined as pathology advanced, particularly notable among cells in the two brain regions most affected early in Alzheimer’s: the entorhinal cortex and hippocampus. The analyses also underscored specific cell types that were especially at risk, such as microglia that perform immune and other supportive roles, oligodendrocytes responsible for producing myelin insulation for neurons, and certain kinds of excitatory neurons.
Risk genes and “chromatin guardians”
Detailed examinations in the paper emphasized how epigenomic regulation paralleled disease-related challenges, Liu notes. The e4 variant of the APOE gene, for instance, is widely recognized as the predominant genetic risk factor for Alzheimer’s. In APOE4 brains, microglia initially reacted to the emerging disease pathology by increasing their epigenomic information, suggesting they were stepping up to their unique role in combating disease. However, as the disease progressed, the cells displayed a dramatic decline in information, signaling deterioration and decay. This reversal was most pronounced in individuals who…
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had a pair of copies of APOE4, instead of merely one. The discoveries, Kellis stated, imply that APOE4 could destabilize the genome of microglia, leading to their burnout.
Another illustration is the destiny of neurons that express the gene RELN and its protein Reelin. Previous investigations, including those by Kellis and Tsai, have indicated that neurons expressing RELN in the entorhinal cortex and hippocampus are particularly susceptible in Alzheimer’s, but foster resilience if they endure. The recent study illuminates their fate by revealing that they suffer early and significant epigenomic data loss as the disease progresses, yet in individuals who retained cognitive resilience, the neurons preserved their epigenomic data.
In another case, the researchers monitored what they informally refer to as “chromatin guardians” because their expression maintains and regulates cells’ epigenomic programs. For example, cells exhibiting greater epigenomic degradation and advanced AD progression showed increased chromatin accessibility in regions that should have been secured by Polycomb repression genes or other gene silencing mechanisms. While resilient cells expressed genes that enhance neural connectivity, epigenomically degraded cells expressed genes associated with inflammation and oxidative stress.
“The message is unmistakable: Alzheimer’s is not solely about plaques and tangles, but about the decay of nuclear organization itself,” Kellis explains. “Cognitive decline arises when chromatin guardians yield ground to the forces of degradation, transitioning from resilience to susceptibility at the most fundamental level of genome regulation.
“And when our neuronal cells lose their epigenomic memory markers and epigenomic data at the most profound level deep within our neurons and microglia, it appears that Alzheimer’s patients also forfeit their memory and cognition at the highest level.”
Other contributors to the paper include Benjamin T. James, Kyriaki Galani, Riley J. Mangan, Stuart Benjamin Fass, Chuqian Liang, Manoj M. Wagle, Carles A. Boix, Yosuke Tanigawa, Sukwon Yun, Yena Sung, Xushen Xiong, Na Sun, Lei Hou, Martin Wohlwend, Mufan Qiu, Xikun Han, Lei Xiong, Efthalia Preka, Lei Huang, William F. Li, Li-Lun Ho, Amy Grayson, Julio Mantero, Alexey Kozlenkov, Hansruedi Mathys, Tianlong Chen, Stella Dracheva, and David A. Bennett.
Support for the research was provided by the National Institutes of Health, the National Science Foundation, the Cure Alzheimer’s Fund, the Freedom Together Foundation, the Robert A. and Renee E. Belfer Family Foundation, Eduardo Eurnekian, and Joseph P. DiSabato.
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