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Could novel chemical compounds help improve immune responses in the brain during Alzheimer’s disease?
William Ralvenius, Ph.D.
Massachusetts Institute of Technology, Picower Institute of Learning and Memory
Cambridge, MA - United States
Background
Recent studies have established the protein PU.1 as a key regulator of the immune response in the brain, during Alzheimer’s. The PU.1 protein is only found inside microglia, which are the most common immune cells in the brain. Microglia help remove toxins from the brain, including high levels of beta-amyloid that often accumulate into plaques as a hallmark of Alzheimer’s disease. Past studies suggest that increased levels of PU.1 cause inflammatory damage in the brain, as seen in multiple laboratory models of brain diseases. Additional studies suggest that genetic variations that reduce PU.1 levels may delay Alzheimer’s disease onset.
Since PU.1 is not found in nerve cells, Dr. William T. Ralvenius proposes that influencing the activity of PU.1 may represent a new potential therapeutic avenue that will specifically reduce harmful immune responses triggered by microglia, while preserving nerve cell function.
Research Plan
In order to conduct their study, Dr. Ralvenius and his colleagues in the lab of Professor Li-Huei Tsai will use their previously established model of induced pluripotent stem cells (iPSCs) obtained from skin tissue of adult individuals with Alzheimer’s disease. Since iPSCs can be reprogrammed into any cell type in the human body, the researchers will use these iPSCs to create microglia in laboratory dishes and use gene editing techniques to reduce or increase PU.1 levels. They will then study the impact of changing the PU.1 levels in microglia in the laboratory dish and in genetically- engineered mouse models of Alzheimer’s disease.
In parallel, the researchers have evaluated over 55,000 chemical compounds in the search for blockers of PU.1 activity, and plan to test the top three candidate compounds. The optimal compound will reduce inflammation while promoting removal of harmful proteins—thus preserving nerve cell function—across several Alzheimer’s disease models. These include iPSCs containing genetic variations similar to those found in people with Alzheimer’s disease, as well as in three dimensional reconstructions of the human brain with microglia and other brain cells, and in genetically engineered mouse models of Alzheimer’s disease. Once the most promising compound has been identified, Dr. Ralvenius’ team also aims to identify genes that associate with healthy microglia function by use of these models.
Impact
This study aims to identify novel compounds that might help delay Alzheimer’s disease onset, or maintain healthy immune responses in the brains of people with Alzheimer’s disease. The work is also likely to generate several new laboratory models and techniques that can be used by other researchers in the field of Alzheimer’s disease and other brain diseases.
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