The oligodendrocyte precursor cell: a new therapeutic target to maintain synaptic integrity in Alzheimer’s disease

The immune system and the nervous system have long been viewed as distinct biological domains. On the contrary, recent work suggests that interactions between the immune system and the brain are critical for neural circuit development and function, and that impairments in these interactions contribute to neurological disorders arising across the lifespan, from autism to Alzheimer’s disease and beyond. My research program focuses on understanding how brain-resident immune cells, such as microglia, interact with other cell types, such as oligodendrocyte precursor cells (OPCs) and neurons, to refine and remodel central circuits in the developing and adult brain. In parallel, we seek to understand how either systemic or localized inflammation contributes to synapse loss in diseases such as Alzheimer’s disease. We generate new viral and genetic tools and apply state-of-the-art experimental approaches, ranging from in vivo multi-photon microscopy to single-cell genomics, to mouse and human brains to address these questions at cellular, molecular, and circuit levels. Our ultimate goal is to contribute to the field’s fundamental understanding of the mechanisms driving synaptic organization, plasticity, and function in the brain, and to inform new therapeutic strategies for treating disorders associated with altered synapses, such as neurodegenerative conditions.

Dr. Lucas Cheadle is an associate professor of neuroscience at Cold Spring Harbor Laboratory (CSHL) and a Howard Hughes Medical Institute Freeman Hrabowski Scholar. Originally from the Chickasaw Nation in rural Oklahoma, Dr. Cheadle completed his high school education at the Oklahoma School of Science and Mathematics in Oklahoma City, where he developed a passion for understanding how sensory experiences impact the brain. Dr. Cheadle then earned a bachelor’s degree from Smith College followed by a PhD from Yale University, both in neuroscience, before training as a postdoctoral fellow with Dr. Michael Greenberg at Harvard Medical School. Dr. Cheadle joined the faculty of CSHL in 2020, where his work merges cutting-edge approaches ranging from in vivo multi-photon microscopy in awake mice to single-cell genomics to define the contributions of immune cells and other non-neuronal cell populations to brain development and function. In parallel with studies of the healthy brain, the Cheadle Lab investigates the mechanisms through which inflammatory signals originating outside of the brain contribute to neurological disorders that arise across the lifespan, from autism to Alzheimer’s disease. The impact of Dr. Cheadle’s research has been recognized with a NIH Director’s New Innovator Award, a Rita Allen Scholar Award, a McKnight Scholar Award, and a Klingenstein-Simons Fellowship Award in Neuroscience.

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, yet effective treatments for this debilitating disorder remain elusive. The deterioration of cognitive function in individuals with AD correlates strongly with a loss of synapses, neuronal structures that support a plethora of brain functions, including the formation and storage of memory. Brain-resident immune cells called microglia are thought to initiate synapse loss in AD by inappropriately removing functional synapses, yet clinical trials aimed at inhibiting synapse elimination in AD patients have yielded disappointing results.  Thus, blocking mechanisms of synapse elimination may, on its own, be insufficient to treat AD.

 "The MIND Prize will allow my laboratory to launch a new direction of research focused on uncovering promising cellular therapeutic approaches for treating Alzheimer’s disease. In particular, we will explore the possibility that boosting mechanisms that protect vulnerable synapses from loss could ameliorate cognitive decline during neurodegeneration."

In this project, we will test the hypothesis that, rather than or in addition to inhibiting synapse removal by microglia, boosting cellular mechanisms that actively protect synapses could be a feasible therapeutic approach to treating AD. In particular, we propose that a class of poorly understood brain cells, oligodendrocyte precursor cells (OPCs), may represent a largely unexplored therapeutic target for ameliorating cognitive decline in AD, and we propose they may do so by actively protecting vulnerable synapses from loss. To test this hypothesis, we will apply brain imaging in live mice, electrophysiology, and behavioral tests of cognitive function to assess how OPCs contribute to disease progression in multiple mouse models of AD, and we will utilize cellular transplantation to determine whether replacing unhealthy OPCs in the AD brain with those from healthy mice restores cognitive function. Finally, we will engage a cutting-edge proteomics strategy to identify the molecular mechanisms through which OPCs actively protect synapses, thereby identifying new therapeutically targetable pathways. The overarching goals of the project are to give rise to a new research field focused on understanding how non-neuronal brain cells contribute to the active preservation of vulnerable synapses during healthy aging and neurodegeneration, and to inform the establishment of new clinical strategies for treating AD.