Changes in neuronal activity alter blood flow to match energy demand with the supply of oxygen and nutrients. This functional hyperemia is maintained by interactions among neurons, vascular cells, and glia. However, how changing neuronal activity prevalent at the onset of neurodegenerative disease affects neurovascular elements is unclear. Here, in mice with photoreceptor degeneration, a model of neuron-specific dysfunction, we combined the assessment of visual function, neurovascular unit structure, and blood-retina barrier permeability. We found that the rod loss paralleled remodeling of the neurovascular unit, comprising photoreceptors, retinal pigment epithelium, and Muller glia. When substantial visual function was still present, blood flow became disrupted and the blood-retina barrier began to fail, facilitating cone loss and vision decline. Thus, in contrast to the established view, the vascular deficit in neuronal degeneration is not a late consequence of neuronal dysfunction but is present early in the course of disease. These findings further establish the importance of vascular deficit and blood-retina barrier function in neuron-specific loss and highlight it as a target for early therapeutic intervention.
Elena Ivanova, Nazia M. Alam, Glen T. Prusky, Botir T. Sagdullaev
Multiple pathways leading to cone death in RD.