Imaging Microglial Homeostasis and Disruption: P2RY12 Radiotracer Development

Inflammation is prominent in several neurodegenerative diseases, including Alzheimer’s disease, and microglial cells are known to play a key role in the inflammatory process. Emerging evidence suggests that dysregulated microglia may influence the onset and progression of the disease, but there remains a critical need to visualize these early-stage molecular changes in the living brain. The development of a P2ry12-selective radiotracer for use with in vivo imaging will provide a novel cell-specific biomarker to visualize homeostatic and dysregulated microglial phenotypes in the living brain.

The cause of Alzheimer’s disease remains unknown despite convincing evidence for the involvement of amyloid beta accumulation, tau tangles, chronic neuroinflammation and oxidative stress. There is a biological process that has a hand in regulating all of these processes. That cellular process is called purinergic signaling, whichrefers to cellular pathways that are activated by nucleotides such as ATP (the energy currency of the cell) and regulate cell signaling pathways involved in inflammation, cell growth, repair and neuronal survival. Studies examining the brains of individuals with Alzheimer’s disease have found there is a protein that is uniquely altered both during the onset of Alzheimer’s disease and in the cells surrounding the amyloid plaques in the brains. This protein belongs to the purinergic signaling family and is called P2Y12R. For therapeutic interventions to start as early as possible, it is necessary to identify biomarkers that serve as an alarm bell that a shift in the brain is occurring from presymptomatic to a symptomatic Alzheimer’s state. Cerebrospinal fluid collection is invasive and brain imaging currently monitors amyloid plaque and tau accumulation—and accumulation of these proteins often occurs after a patient already has developed memory impairments. Identifying a protein that signaled Alzheimer’s disease before the accumulation of plaques and tangles would help to identify individuals with the greatest risk of developing Alzheimer’s disease for the purposes of early therapeutic intervention.