In the Alzheimer’s affected brain, abnormal
levels of the beta-amyloid protein clump together to form plaques (seen
in brown) that collect between neurons and disrupt cell function.
Abnormal collections of the tau protein accumulate and form tangles
(seen in blue) within neurons, harming synaptic communication between
nerve cells.
Credit: National Institute on Aging, NIH
MIT researchers have performed the first
comprehensive analysis of the genes that are expressed in individual
brain cells of patients with Alzheimer's disease. The results allowed
the team to identify distinctive cellular pathways that are affected in
neurons and other types of brain cells.
This analysis could offer many potential new drug targets for
Alzheimer's, which afflicts more than 5 million people in the United
States.
"This study provides, in my view, the very first map for going after
all of the molecular processes that are altered in Alzheimer's disease
in every single cell type that we can 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 Broad
Institute of MIT and Harvard. "It opens up a completely new era for
understanding Alzheimer's."
The study revealed that a process called axon myelination is
significantly disrupted in patients with Alzheimer's. The researchers
also found that the brain cells of men and women vary significantly in
how their genes respond to the disease.
Kellis and Li-Huei Tsai, director of MIT's Picower Institute for
Learning and Memory, are the senior authors of the study, which appears
in the May 1 online edition of Nature. MIT postdocs Hansruedi Mathys and Jose Davila-Velderrain are the lead authors of the paper.
Single-cell analysis
The researchers analyzed postmortem brain samples from 24 people who
exhibited high levels of Alzheimer's disease pathology and 24 people of
similar age who did not have these signs of disease. All of the subjects
were part of the Religious Orders 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 of
brain tissue, but these studies don't distinguish between cell types,
which can mask changes that occur in less abundant cell types, Tsai
says.
"We wanted to know if we could distinguish whether each cell type has
differential gene expression patterns between healthy and diseased
brain tissue," she says. "This is the power of single-cell-level
analysis: You have the resolution to really see the differences among
all the different cell types in the brain."
Using the single-cell sequencing approach, the researchers were able
to analyze not only the most 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 distinct gene
expression differences in Alzheimer's patients.
Some of the most significant changes occurred in genes related 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
oligodendrocytes, the cells that produce myelin.
Most of these cell-type-specific changes in gene expression occurred
early in the development of the disease. In later stages, the
researchers found that most cell types had very similar 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.
Sex differences
The researchers also discovered correlations between gene expression
patterns and other measures of Alzheimer's severity such as the level of
amyloid plaques and neurofibrillary tangles, as well as cognitive
impairments. This allowed them to identify "modules" of genes that
appear to be linked to different aspects of the disease.
"To identify these modules, we devised a novel strategy that involves
the use of an artificial neural network and which allowed us to learn
the sets of genes that are linked to the different aspects of
Alzheimer's disease in a completely unbiased, data-driven fashion,"
Mathys says. "We anticipate that this strategy will be valuable to also
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 from male and female
Alzheimer's patients. They found that excitatory neurons and other brain
cells from 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.
"That's when we realized there's something very interesting going on. We were just shocked," Tsai says.
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 from the Religious Orders Study group, the
researchers found that female subjects with severe memory deficits had
much more white matter damage than matched male subjects.
More study is needed to determine why men and women respond so
differently to Alzheimer's disease, the researchers say, and the
findings could have implications for developing and choosing treatments.
"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
non-neuronal myelinating cells as potentially having a role. 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," Davila-Velderrain says.
The researchers are now using mouse and human induced pluripotent
stem cell models to further study some of the key 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 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.
The research was funded by the National Institutes of Health, the JBP Foundation, and the Swiss National Science Foundation.
Journal Reference:
- Hansruedi Mathys, Jose Davila-Velderrain, Zhuyu Peng, Fan Gao, Shahin Mohammadi, Jennie Z. Young, Madhvi Menon, Liang He, Fatema Abdurrob, Xueqiao Jiang, Anthony J. Martorell, Richard M. Ransohoff, Brian P. Hafler, David A. Bennett, Manolis Kellis & Li-Huei Tsai. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature, 2019 DOI: 10.1038/s41586-019-1195-2
Courtesy: ScienceDaily
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