Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of
Alejandra Bosco1, Cesar O Romero2, Kevin T Breen2
1Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA alejandra.bosco@neuro.utah.edu.
Abstract:
Microglia serve key homeostatic roles, and respond to neuronal perturbation and decline with a high spatiotemporal resolution. The course of all chronic CNS pathologies is thus paralleled by local microgliosis and microglia activation, which begin at early stages of the disease. However, the possibility of using live monitoring of microglia during early disease progression to predict the severity of neurodegeneration has not been explored. Because the retina allows live tracking of fluorescent microglia in their intact niche, here we investigated their early changes in relation to later optic nerve neurodegeneration. To achieve this, we used the DBA/2J mouse model of inherited glaucoma, which develops progressive retinal ganglion cell degeneration of variable severity during aging, and represents a useful model to study pathogenic mechanisms of retinal ganglion cell decline that are similar to those in human glaucoma. We imaged CX3CR1(+/GFP) microglial cells in vivo at ages ranging from 1 to 5 months by confocal scanning laser ophthalmoscopy (cSLO) and quantified cell density and morphological activation. We detected early microgliosis at the optic nerve head (ONH), where axonopathy first manifests, and could track attenuation of this microgliosis induced by minocycline. We also observed heterogeneous and dynamic patterns of early microglia activation in the retina. When the same animals were aged and analyzed for the severity of optic nerve pathology at 10 months of age, we found a strong correlation with the levels of ONH microgliosis at 3 to 4 months. Our findings indicate that live imaging and monitoring the time course and levels of early retinal microgliosis and microglia activation in glaucoma could serve as indicators of future neurodegeneration severity.
Insights
Live monitoring of microglia in the eye can predict neurodegeneration severity in glaucoma. Early changes in microglia activation at the optic nerve head correlate with later optic nerve damage.
Area of Science:
- Neuroscience
- Ophthalmology
- Immunology
Background:
- Microglia are crucial for central nervous system homeostasis and respond rapidly to neuronal damage.
- Microgliosis and microglia activation are early hallmarks of chronic central nervous system pathologies, including neurodegeneration.
- The potential of live microglia monitoring for predicting neurodegeneration severity has not been previously investigated.
Purpose of the Study:
- To investigate early changes in microglia in relation to optic nerve neurodegeneration.
- To determine if live monitoring of microglia can predict the severity of neurodegeneration in an inherited glaucoma model.
Main Methods:
- Utilized the DBA/2J mouse model of inherited glaucoma.
- Imaged fluorescent microglia (CX3CR1(+/GFP)) in vivo using confocal scanning laser ophthalmoscopy (cSLO) from 1 to 5 months of age.
- Quantified microglial cell density and morphological activation, particularly at the optic nerve head (ONH).
Main Results:
- Early microgliosis was detected at the optic nerve head (ONH), the site of initial axonopathy.
- Minocycline treatment was shown to attenuate this early microgliosis.
- Heterogeneous and dynamic patterns of microglia activation were observed in the retina.
- A strong correlation was found between ONH microgliosis at 3-4 months and optic nerve pathology severity at 10 months of age.
Conclusions:
- Live imaging of microglia in the retina provides insights into early disease progression in glaucoma.
- Monitoring the time course and levels of retinal microgliosis and microglia activation can serve as predictive indicators of future neurodegeneration severity in glaucoma.
