Alzheimer’s genome-wide association studies (GWAS) that compare the genetic material from individuals with Alzheimer’s with that of healthy individuals have implicated genes involved in regulating the immune system as a risk factor for neurodegeneration. Emerging evidence shows that dysregulation of the brain’s immune system, and its microglial cells, plays an important role in the onset and progression of Alzheimer’s disease. Studies have shown that activated microglia surround amyloid plaques, the classic pathology associated with Alzheimer’s disease, and implicate inflammatory pathways in disease progression. Investigations of the role glial cells play in Alzheimer’s disease have been hampered by an inability to image these cells in the brains of living patients. Imaging microglia-specific molecules has a key role to play in defining neuroinflammation as it relates to glial function, and the consequence of glial activation in the living human brain. The goal of this project is to develop a Positron Emission Tomography (PET) radiotracer to quantify changes in microglia molecular activity in the living brain as a reflection of the pathophysiological changes associated with Alzheimer’s disease. Our research has identified a new molecular target for PET imaging—the activation of microglia called SH2 Domain-containing Inositol Phosphatase 1 (SHIP1). Developing a SHIP1-specific PET radiotracer will pave the way for imaging microglial dynamics associated with Alzheimer’s disease.
Cure Alzheimer’s Fund has recognized the importance of studying the relationship between the brain and its immune system in Alzheimer’s disease. The immune system is likely the next target of drugs to treat this intractable disease. There are huge gaps that exist in this emerging field, and CureAlz is committed to filling them by linking experts across the field in a consortium that will work together. The goal of this proposal is to begin filling a technology gap. More specifically, this proposal addresses the essential need to be able to see into the AD brain, since we cannot access it through biopsy. The ability to image immune processes that are elucidated and being studied in model systems and in post-mortem brain tissue from consortium members supported by CureAlz is essential. However, the data magnitude is overwhelming and there is no clear, persuasive starting point for the technology development. Rather than make assumptions about what targets in the brain immune system can and should be imaged, we will mine existing public and CureAlz scientist data to prioritize targets for imaging the brain. We will use this process to develop a road map to the technologies of the future for brain immune imaging. Ultimately, these road maps will lead to new radiotracers for brain imaging to translate the basic research knowledge to patient observation, and ultimately care and treatment. This proposal is a critical nine-month primer to the launch of a full-scale imaging agent development project.