Genomics and lab studies reveal various findings, such as the vital role of Reelin in neuronal vulnerability, and the significance of choline and antioxidants in maintaining cognition.
A recent study from MIT published in Nature sheds light on how specific cells and circuits become susceptible in Alzheimer’s disease and explores factors that may contribute to resilience against cognitive decline despite the presence of disease pathology. By comparing gene expression in multiple brain regions of individuals with and without Alzheimer’s disease, the researchers identified potential targets for interventions to support cognition and memory.
While brain cells share the same DNA, their unique identities and functions are determined by how their genes are expressed. The study analyzed gene expression variances in over 1.3 million cells from 70 different cell types across six brain regions of 48 donors, 26 with Alzheimer’s and 22 without. This extensive analysis provides insight into how brain cell activity changes in Alzheimer’s disease based on cell type, brain region, disease pathology, and cognitive function.
Co-senior author Li-Huei Tsai emphasized the need to understand the vulnerability of specific brain regions in Alzheimer’s and how different cell types within these regions may respond differently. The study’s novel approach allows for a deeper investigation into this complexity.
Co-senior author Manolis Kellis compared their technique of analyzing gene expression to a highly advanced “microscope” that reveals intricate biological changes at the cellular level in response to Alzheimer’s pathology. This information, when linked to patients’ cognitive status, can offer insights into preserving cognitive function.
The study, led by Hansruedi Mathys, Carles Boix, and Leyla Akay, focused on analyzing various brain regions such as the prefrontal cortex, entorhinal cortex, hippocampus, among others, using brain samples from the Religious Order Study and Rush Memory and Aging Project.
Neural vulnerability and Reelin
The research identified specific excitatory neurons in regions like the hippocampus and entorhinal cortex that were significantly reduced in individuals with Alzheimer’s, impacting cognitive performance. These neurons were found to be part of a shared neuronal circuit and linked to the Reelin protein, indicating a potential association between their loss and cognitive decline.
Reelin has gained attention in Alzheimer’s research due to a study involving a man with a Reelin gene mutation who maintained cognitive health despite a family history of early-onset Alzheimer’s. This suggests a possible protective role of Reelin, although its precise mechanism remains unclear.
Resilience associated with choline metabolism in astrocytes
The study also revealed that astrocytes expressing genes related to antioxidant activity, choline metabolism, and polyamine biosynthesis were linked to preserved cognition in the presence of tau and amyloid pathology. Previous research supporting the benefits of choline supplementation in astrocytes further reinforced these findings.
New analysis method, open dataset
To analyze the extensive single-cell data, the researchers developed a new methodology based on groups of coordinately-expressed genes, allowing for a more in-depth exploration of gene expression patterns.
The article discusses the identification of coordinated gene expression patterns within functionally-related genes in the same module. The researchers found that despite the vast number of possible combinations of genes in cells, they observed a smaller subset of coordinated changes that can lead to more robust insights. By recognizing these coordinated patterns, scientists can infer significant changes based on multiple genes within the same functionally-connected module.
An analogy was provided to explain this concept: Just as people have numerous joints in their bodies allowing for various movements, they typically engage in coordinated movements like walking, running, or dancing. Similarly, the new method enables the identification of coordinated gene expression programs as a cohesive group.
While some important findings have already been reported from the dataset, the researchers believe that there are still many more potentially significant discoveries waiting to be uncovered. To aid in this discovery process, the team has made analytical and visualization tools available on Kellis’s website to explore the data further.
Looking ahead, the researchers are focusing on studying the control circuitry linked to the differentially expressed genes to comprehend the genetic variants, regulators, and other factors that could be targeted to reverse disease circuitry across various brain regions, cell types, and disease stages.
The study involved additional authors such as Ziting Xia, Jose Davila Velderrain, Ayesha P. Ng, Xueqiao Jiang, Ghada Abdelhady, Kyriaki Galani, Julio Mantero, Neil Band, Benjamin T. James, Sudhagar Babu, Fabiola Galiana-Melendez, Kate Louderback, Dmitry Prokopenko, Rudolph E. Tanzi, and David A. Bennett. The research was supported by various organizations, including the National Institutes of Health, The Picower Institute for Learning and Memory, The JPB Foundation, the Cure Alzheimer’s Fund, The Robert A. and Renee E. Belfer Family Foundation, Eduardo Eurnekian, and Joseph DiSabato.
