Exploring the divergence The neurovascular unit in the eye and brain in diabetes and Alzheimer's disease

This thesis investigates alterations of the neurovascular unit (NVU) in the retina and brain, focusing on diabetes mellitus (DM) and Alzheimer’s disease (AD). The retina and brain are protected by highly selective vascular barriers, the blood-retinal barrier (BRB) and blood-brain barrier (BBB), which are regulated by the NVU, a multicellular complex of endothelial cells, pericytes, glia, and neurons. Disruption of the NVU can lead to vascular leakage and neuronal damage. Although type 2 DM increases the risk of AD, the mechanisms linking these diseases through NVU dysfunction remain unclear.
A novel zebrafish model was developed to study BBB integrity under hyperglycaemic conditions. Combining live imaging, fluorescent reporters, and electron microscopy, this model enables detailed assessment of vascular permeability and tight junction integrity, offering a valuable platform to study barrier breakdown in diabetic and neurovascular diseases.
In a 5xFAD mouse model of AD, retinal changes included synaptic dysfunction, gliosis, and retinal thickening, but only minimal amyloid accumulation and no activation of JNK signaling, contrasting with pronounced brain pathology. This suggests divergent retinal and cerebral disease mechanisms.
Analysis of human tissues revealed distinct NVU alterations in DM and AD. DM affected retinal and brain vasculature differently, while combined DM and AD produced the most severe NVU disruption. An optimized immunofluorescence protocol enabled detailed 3D visualization of retinal pericytes, revealing significant pericyte loss in DM and diabetic retinopathy, with subtler brain changes. Overall, the findings highlight tissue-specific NVU pathologies and emphasize the need for further research into barrier dysfunction in DM and AD.