Role of Type I Interferon in Alzheimer’s Disease
Alzheimer’s disease (AD) is a devastating disease with no cure. Often, the brains of AD patients have ongoing inflammation that fuels the disease. This project will study a new family of cytokines (ie, proteins regulating the immune system) which we recently detected in AD brains. Our goal is to obtain knowledge about how inflammation worsens AD, and also to identify targets for effective treatments.
Summary: In Alzheimer's brains, not only do toxic proteins known as amyloid-beta (Aβ) and tau clump together, but also glia cells of the brain’s immune system fire up abnormally. The resulting inflammation is more and more recognized as one of the drivers for Alzheimer’s disease (AD) progression. Having identified a new family of immune molecules as part of the AD brain inflammation, we will reveal its role in AD pathogenesis and find out how it damages neurons and memory.
Details: Unusual aggregation of proteins, including Aβ plaques outside the cells and tau tangles inside the neurons, marks the brains of AD patients. Now we know of a third feature strongly associated with AD, inflammation, which involves activated glia cells and abnormal expression of many immune molecules. Most of these molecules found in AD brain are normally expressed by immune cells in other parts of the body to fight against microbial infections or respond to injury. It is now recognized that the overactive immune response inside the brain is causing much damage to the neurons and the functions of the brain. Although the importance of such inflammation is clear, we do not know enough about the immune pathways involved to come up with good strategies to target the crucial ones on the spot.
We have previously found that certain amyloid fibrils can activate immune cells and trigger a unique inflammatory response that resembles one against viral infections in other parts of the body. Such response induces the production of type I interferon, a family of immune molecules not yet linked to the inflammation in AD brains. We since have detected obvious activation of the signaling pathway controlled by type I interferon in both mouse and human AD brain tissues. Blocking this pathway in AD mouse model effectively diminished the ongoing inflammation in the brain. Importantly, many clinical studies already point to a negative effect of type I interferon on brain functions in human patients. This made us determined to study precisely how type I interferon affects AD pathogenesis and whether it can serve as a therapeutic target.
Using two different AD mouse models, we will test whether type I interferon production is required for full AD development, and whether increased levels of type I interferon can speed up the ongoing disease process. To understand the importance of this molecule in overall brain inflammation, we will do genome-wide gene expression analysis to identify pathways controlled by type I interferon. We will also test whether type I interferon activates microglia, the brain’s resident immune cells, to strip neurons of their synapses, or connections through which they communicate with one another, which would cause memory and cognitive problems.
We hope that completion of the proposed studies will firmly establish the pathogenic role of type I interferon in AD and solidify type I interferon and its downstream factors as molecular targets for next-generation therapeutics.
About the Researcher
Dr. Wei Cao is an associate professor in the Huffington Center on Aging and the Department of Molecular and Human Genetics at Baylor College of Medicine. Wei grew up in Beijing, China, and attended Tsinghua University to study biology as an undergraduate. After traveling to the United States, Wei entered the graduate program in the University of North Carolina at Chapel Hill, where she obtained her PhD in biochemistry studying protein biogenesis. Wei next trained with Dr. Michael B. A. Oldstone in The Scripps Research Institute, in La Jolla, CA, as a postdoc fellow in molecular virology. Following that, she joined a biotech company in California, working in flu vaccine development and production. Later, Wei moved to Texas and worked in the MD Anderson Cancer Center to start a career in Immunology research. She became an assistant professor in the Department of Immunology, studying innate immune responses pertinent to viral infection and autoimmunity. Most recently, Wei joined the Baylor College of Medicine to focus her research on neuroinflammation in neurodegenerative diseases. By applying the key findings from previous studies and expertise obtained studying immune pathologies, Dr. Cao is aiming to make an impact in AD research as well as therapeutic developments.
As a biologist, I’ve always been fascinated by the many faces of proteins. Different from DNA, whose encoded information is explicit, proteins come in different shapes, spliced forms and post-translational modifications, locate to different cellular sites, and switch binding partners under different conditions. Proteins execute the commands from the genes to control cellular functions, and yet proteins can go rogue themselves.
I have worked with proteins for many years. I studied signals governing protein trafficking inside cells as a graduate student; identified a cell surface receptor utilized by a group of killer viruses to invade cells when I was a postdoc; and produced viral proteins as antigens to trigger immune protection in an upcoming flu season when working in a Biotech company. As an immunologist, I studied the way proteins act as innate immune sensors to detect viruses and elicit protective immune response from specialized immune cells.
Several years ago, by serendipity, we ended up working with protein preparations that precipitated in solution yet potently stimulated anti-viral immune response in the specialized immune cells we were researching. After careful examination and a series of controlled studies, we found that the immunogenic protein preparations shared biochemical features with amyloid fibrils, the type of aggregates found in the AD brain. It was a rather unexpected finding, and never reported before. After extending the molecular characterization and carrying out further immunological investigations, we published the discoveries. Interestingly, the anti-viral innate immune property of amyloid was recently confirmed by a group studying E. coli curli, a bacterial amyloid protein.
At that point, Alzheimer’s disease (AD) still was remote to me in life. However, my research findings prompted me to look at their relevance in AD and other neurodegenerative diseases where protein misfolding and neuroinflammation prevail. After reading literature on these horrendous diseases, I suddenly realized that perhaps my paternal grandma was suffering from AD when she lived with my family decades ago. I can recall that, in her late 70s, she stared at the roof of our neighboring building for hours, and got lost and found multiple times in the neighborhood. No one ever bothered to diagnose her; rather, everyone was taking her as a normal senile case. Yet, something was wrong, and the family was stressed out. How much I wish to go back in time and find some relief for her now!
With a strong belief in the basic principles and potential implications of our previous discoveries, I took a leap and joined the faculty of the Huffington Center on Aging at the Baylor College of Medicine to dedicate my efforts to studying neuroinflammation in AD pathogenesis. So far, we have obtained experimental evidence to substantiate my initial hypothesis and are getting ready to answer the ultimate questions – is this anti-viral immune pathway pathogenic in AD? How does it participate in the AD process? Is it a good target for therapies curtailing neuroinflammation?
I am grateful to BrightFocus Foundation for its support of my proposal. For me, it not only enables the science I put forward, but also endorses my entry into the field of AD research. To all the generous donors, thank you.
First published on: June 26, 2018
Last modified on: July 3, 2018