A comprehensive map of how alzheimer’s affects the brain ledderhose disease treatment mit news

“This study provides, in my view, the very first map for going after all of the ledderhose disease treatment molecular processes that are altered in Alzheimer’s disease in every single cell type that we can ledderhose disease treatment now reliably characterize,” says Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory and of the ledderhose disease treatment Broad Institute of MIT and Harvard. “It opens up a completely new era for understanding Alzheimer’s.”

The researchers analyzed postmortem brain samples from 24 people who ledderhose disease treatment exhibited high levels of Alzheimer’s disease pathology and 24 people of similar age who ledderhose disease treatment did not have these signs of disease. All of the subjects were part of the Religious Orders ledderhose disease treatment Study, a longitudinal study of aging and Alzheimer’s disease. The researchers also had data on the subjects’ performance on cognitive tests.

The MIT team performed single-cell RNA sequencing on about 80,000 cells from these subjects. Previous studies of gene expression in Alzheimer’s patients have measured overall RNA levels from a section ledderhose disease treatment of brain tissue, but these studies don’t distinguish between cell types, which can mask changes that occur in less abundant cell ledderhose disease treatment types, Tsai says.

Using the single-cell sequencing approach, the researchers were able to analyze not only the most ledderhose disease treatment abundant cell types, which include excitatory and inhibitory neurons, but also rarer, non-neuronal brain cells such as oligodendrocytes, astrocytes, and microglia. The researchers found that each of these cell types showed ledderhose disease treatment distinct gene expression differences in Alzheimer’s patients.

Some of the most significant changes occurred in genes related ledderhose disease treatment to axon regeneration and myelination. Myelin is a fatty sheath that insulates axons, helping them to transmit electrical signals. The researchers found that in the individuals with Alzheimer’s, genes related to myelination were affected in both neurons and ledderhose disease treatment oligodendrocytes, the cells that produce myelin.

Most of these cell-type-specific changes in gene expression occurred early in the development ledderhose disease treatment of the disease. In later stages, the researchers found that most cell types had very similar ledderhose disease treatment patterns of gene expression change. Specifically, most brain cells turned up genes related to stress response, programmed cell death, and the cellular machinery required to maintain protein integrity.

“To identify these modules, we devised a novel strategy that involves the use of ledderhose disease treatment an artificial neural network and which allowed us to learn ledderhose disease treatment the sets of genes that are linked to the different ledderhose disease treatment aspects of Alzheimer’s disease in a completely unbiased, data-driven fashion,” Mathys says. “We anticipate that this strategy will be valuable to also ledderhose disease treatment identify gene modules associated with other brain disorders.”

The most surprising finding, the researchers say, was the discovery of a dramatic difference between brain cells ledderhose disease treatment from male and female Alzheimer’s patients. They found that excitatory neurons and other brain cells from ledderhose disease treatment male patients showed less pronounced gene expression changes in Alzheimer’s than cells from female individuals, even though those patients did show similar symptoms, including amyloid plaques and cognitive impairments. By contrast, brain cells from female patients showed dramatically more severe gene-expression changes in Alzheimer’s disease, and an expanded set of altered pathways.

So far, it is unclear why this discrepancy exists. The sex difference was particularly stark in oligodendrocytes, which produce myelin, so the researchers performed an analysis of patients’ white matter, which is mainly made up of myelinated axons. Using a set of MRI scans from 500 additional subjects ledderhose disease treatment from the Religious Orders Study group, the researchers found that female subjects with severe memory deficits ledderhose disease treatment had much more white matter damage than matched male subjects.

“There is mounting clinical and preclinical evidence of a sexual ledderhose disease treatment dimorphism in Alzheimer’s predisposition, but no underlying mechanisms are known. Our work points to differential cellular processes involving non-neuronal myelinating cells as potentially having a role. It will be key to figure out whether these discrepancies ledderhose disease treatment protect or damage the brain cells only in one of ledderhose disease treatment the sexes — and how to balance the response in the desired direction ledderhose disease treatment on the other,” Davila-Velderrain says.

The researchers are now using mouse and human induced pluripotent ledderhose disease treatment stem cell models to further study some of the key ledderhose disease treatment cellular pathways that they identified as associated with Alzheimer’s in this study, including those involved in myelination. They also plan to perform similar gene expression analyses for ledderhose disease treatment other forms of dementia that are related to Alzheimer’s, as well as other brain disorders such as schizophrenia, bipolar disorder, psychosis, and diverse dementias.