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Single-Cell Transcriptomic Study Maps Changes That Arise in Brain During Alzheimer's Disease

NEW YORK (GenomeWeb) – A single-cell transcriptomic study uncovered Alzheimer's disease-linked gene expression changes that occur in different brain cell types.

Researchers from the Massachusetts Institute of Technology profiled more than 80,000 single cells from nearly 50 individuals with varying degrees of pathology associated with Alzheimer's disease.

"We wanted to know if we could distinguish whether each cell type has differential gene expression patterns between healthy and diseased brain tissue," co-senior author Li­Huei Tsai from MIT said in a statement. "This is the power of single­cell­level analysis: You have the resolution to really see the differences among all the different cell types in the brain."

The researchers uncovered cell-type-specific transcriptional changes that occur early on in disease development, though noted that many of these changes affected similar cellular processes. The results were reported in Nature today.

Using samples from the Religious Order Study — a longitudinal cohort of aging and dementia — Tsai and her colleagues profiled postmortem tissue from the prefrontal cortex of 24 individuals with heightened β-amyloid and other markers of Alzheimer's disease and 24 individuals with low or no β-amyloid levels. From these samples, they generated 80,660 droplet-based single-nucleus RNA-seq profiles.

Based on known gene markers, the researchers identified various cell types among these profiles, including excitatory neurons, inhibitory neurons, astrocytes, and more.

By comparing individuals with Alzheimer's disease-linked pathology and no such pathology, the researchers identified, 1,031 differentially expressed genes that affected all the major cell types. They confirmed these differentially expressed genes in a bulk cell analysis.

The vast majority — 95 percent — of these differentially expressed genes were only affected in neurons or in one glial cell type, which the researchers said suggested strong cell-type specificity.

However, they also noted that the top differentially expressed genes are associated with similar cellular processes. For instance, they found that LINGO1, a top differentially expressed gene that is upregulated in excitatory neurons and oligodendrocytes, is a negative regulator of neuronal survival, axonal integrity, and myelination, while another top differentially expressed gene, ERBB2IP, is needed for axon remyelination.

This, the researchers said, indicates that all major cell types in the brain are affected by Alzheimer's disease pathology at the transcriptional level, but that the expression differences and directionality can vary by cell type.

When they then compared cells from individuals with early-stage disease to those without disease, the researchers found that large-scale transcriptional changes occur before the arrival of more severe pathological features. They noted that the difference between this early-stage and no disease groups was similar to the difference between late-stage and no disease groups, underscoring that major transcriptional changes occur early on.

Using a self-organizing map-based approach, the researchers also examined associations between gene expression, cell type, and disease phenotype, finding a number of gene-trait correlation modules.

They also noted that some of these differences appeared to vary by gender. Excitatory neurons and other cells from female individuals, they found, had more dramatic gene expression changes than cells from male individuals, even when those individuals exhibited similar symptoms.

"There is mounting clinical and preclinical evidence of a sexual dimorphism in Alzheimer's predisposition, but no underlying mechanisms are known. Our work points to differential cellular processes involving non­neuronal myelinating cells as potentially having a role," co-first author Jose Davila­-Velderrain from MIT said in a statement. "It will be key to figure out whether these discrepancies protect or damage the brain cells only in one of the sexes — and how to balance the response in the desired direction on the other."