Ass.Prof. Tsai-Yi Lu, Ph.D.
University of Virginia
School of Medicine
Programm
“Oligodendrocyte lineage dyshomeostasis during brain injury and Alzheimer’s disease”
Our brain relies on homeostatic interactions between neurons and a diverse population of glial cells to execute daily functions and enable plasticity throughout life. For example, myelin-producing glia, known as oligodendrocytes, ensheath neuronal axons with myelin sheaths to accelerate information transfer between different brain regions and provide metabolic support to energy-demanding axons. Emerging evidence suggests that oligodendrocyte pathology and myelin loss are common and early features in brains affected by Alzheimer’s disease (AD), potentially contributing to cognitive deficits and accelerating axonal degeneration. However, the AD-associated factors that contribute to oligodendrocyte-related pathology remain unclear. We previously discovered that norepinephrine (NE), a neurotransmitter released by noradrenergic axons in the central nervous system (CNS), influences the generation of oligodendrocytes by regulating calcium signaling in their resident adult progenitor cells, known as oligodendrocyte precursor cells (OPCs). Interestingly, noradrenergic axons are among the earliest affected neurons in AD, and degeneration of the noradrenergic system is strongly associated with cognitive decline in patients. Using in vivo two-photon imaging, genetic fate tracing, and tRNA sequencing, we found that OPC calcium signaling is severely disrupted in the aggressive AD mouse model 5xFAD, and oligodendrocytes generated in these mice exhibit abnormalities in myelin sheath formation, potentially due to impaired protein synthesis and translation. This phenotype is distinct from the OPC response to general brain injury, in which OPCs transform into “reactive” states and exhibit heightened calcium influx near laser-induced lesions. Together, these findings reveal distinct context-dependent disruptions of oligodendrocyte lineage homeostasis and highlight potential therapeutic targets for restoring myelin integrity in neurodegenerative disease and brain injury.
Host: Vered KELLNER
Contact for questions: Helmut KUBISTA