The human brain contains about 100 billion individual cells that make up a variety of cellular structures in the interconnected and densely packed landscapes of the human brain. For researchers looking for specific causes of impairment from Alzheimer’s disease and other types of dementia, the complexity of the brain and the diversity of the molecular underpinnings of these diseases have made it difficult to develop preventive strategies and treatments.
How do you break up such a complex? A promising answer thanks to the latest technology and analytical techniques: start simple.
Understanding the origins of Alzheimer’s disease at the cellular level
“We know very little about how Alzheimer’s disease develops,” Lu Zhang said.Ph.DFaculty member Responsible for single-cell experimental design and data analysis in the Department of Neurology at Yale University School of Medicine. “In order to understand what happens to people with such a complex disease, we need to start at the cellular level. This should include looking at the gender differences that exist in the individual cells of women and men.”
In a major step towards this crucial understanding, Women’s Health Research at Yale University is now collaborating with Zhang and Stephen StreetmatterMaster’s, Ph.Ddirector of the Yale Alzheimer’s Disease Research Center (ADRC), to reveal, for the first time, gender differences in the origins of Alzheimer’s disease by studying single cells.
“By understanding the subtle differences between cell populations in Alzheimer’s disease, we can build on our knowledge of the disorders that cause cell death and how they relate to disease symptoms such as cognitive dysfunction,” said Strittmatter, M.D., Professor of Neurology at Vincent Coates and Professor of Neurology at Vincent Coates. Neurology. “Knowledge like this has the potential to identify hidden biological clues and produce new therapeutic targets that will benefit women and men who suffer or are at risk of developing this devastating disease.”
What is Alzheimer’s disease?
The basic units of the nervous system, including the brain and spinal cord, are called neurons or neurons. With a few exceptions, these cells, which communicate electrically with other cells, do not reproduce normally and replace themselves like other cells in the body. When nerve cells are damaged or die at accelerated rates, this is called neurodegeneration.
Alzheimer’s disease is the most common neurodegenerative disease, and there is currently no effective treatment. Symptoms include progressive memory loss and cognitive impairment, with significant impact on the daily functioning of those suffering from the disease and on the lives of their caregivers.
Estimated 6.2 million People in the United States have Alzheimer’s disease, about two-thirds of whom are women . In addition, women are more likely to contract the disease , which is attributable to more than a longer life expectancy than that of men. One in five women 65 and older is at risk, compared to one in 11 men . Women with Alzheimer’s disease also have more severe cognitive symptoms and neurodegeneration.
Alzheimer’s disease occurs when several cellular processes break down. For example, accumulations of certain proteins, known as beta-amyloid plaques, around neurons can reduce their ability to communicate with each other and effectively transmit messages within the brain. The cells of people with Alzheimer’s disease also have an imbalance in their ability to transport nutrients due to the formation of disease structures known as synapses. Furthermore, individuals with Alzheimer’s disease may experience inflammation in the nervous system. Researchers are exploring how plaques, tangles, and inflammation relate to each other and cause disease.
Many types of cells contribute to Alzheimer’s disease
What has made treating Alzheimer’s disease particularly difficult is that it involves many types of cells, including neurons, cells that insulate neurons called glial cells, and disease-fighting immune cells. Not only do malfunctions in each of these cell types contribute to disease on their own, but these cell types also interact with each other, further complicating our understanding of disease progression.
It is also currently unclear how the cellular mechanisms underlying Alzheimer’s disease differently contribute to symptoms in women and men. Thus, an accurate understanding of how single cells of different types function in health and disease states in women and men has the potential to open doors for gender-specific Alzheimer’s treatment.
Leveraging single-cell analysis to study Alzheimer’s disease
Researchers have recently developed ways to analyze the subtle differences between individual cells, producing vast amounts of genetic data that can reveal important insights about cell types and diseases. The techniques, collectively called single-cell analysis, provide a unique opportunity to discover different potential origins of the disease in women and men.
In partnership with Women’s Health Research at Yale University and with support from the Werth Family Foundation, Zhang and Strittmatter are using single-cell analysis to reveal sex-specific molecular pathways in Alzheimer’s disease, focusing on abnormalities and inflammation of the central nervous system.
In a previous study, Zhang and Strittmatter demonstrated that they can successfully use single-cell analysis to characterize brains from individuals with and without Alzheimer’s disease. Their preliminary data suggests that people with Alzheimer’s disease have a larger type of glial cell involved in immune responses in an area of the brain that is strongly affected by a disease called the middle temporal gyrus.
The researchers are now building on and extending this work to discover how subpopulations of neuronal, glial, and immune cell types contribute differently to Alzheimer’s disease on the basis of gender.
“There must be a reason why Alzheimer’s disease is more severe in women and why women are at greater risk,” Chang said. “What happens at the cellular level? What are the different molecular pathways that lead to disease? These are the kinds of questions we ask and answer.”
By studying individual brain cells of people with or without Alzheimer’s disease, researchers will be able to identify the sex-specific cell populations and signaling pathways that changed during the development of Alzheimer’s disease. These findings will form the basis for future studies to target these cells and try to help women and men avoid or slow the progression of the disease.
In addition, Zhang and Strittmatter will study cerebrospinal fluid (CSF) cells in patients with Alzheimer’s disease to identify potential genetic shifts in the immune system between the sexes and help diagnose and monitor the disease. This will provide the first complete account of all gene activity at the single-cell level across the central nervous system in Alzheimer’s disease, which may shed light on why women experience more severe symptoms and help develop gender-specific targets for treatment.
Such efforts have only recently begun to focus on the impact of specific diseases, Zhang said. She and her colleagues will openly share their data, leading to the creation of the first cellular roadmap of a major region of the human brain with Alzheimer’s disease. They will be able to provide this model and single-cell technology support to other researchers working in other aspects of biology and disease.
“In order to help people, we must first understand who we are and what is happening to us at the most basic level,” Zhang said. “This starts with our cells.”
Originally posted on March 17, 2020; Updated May 11, 2022