Differential pericyte pathology in the human retina and brain in diabetes mellitus and Alzheimer’s disease

Introduction: In diabetic retinopathy, pericyte dysfunction, pericyte loss, and inner blood-retinal barrier (iBRB) dysfunction contribute to neurovascular unit (NVU) impairment. Diabetes mellitus (DM) is also associated with increased risk of Alzheimer's disease (AD), and it has been hypothesized that DM-induced NVU impairment in brain capillaries, including pericyte dysfunction, may contribute to AD pathogenesis. In the present hypothesis-generating explorative study, we investigated pericyte characteristics in the iBRB in patients with type 2 DM with or without diabetic retinopathy (DR), and in the blood-brain barrier (BBB) in type 2 DM and AD. Methods: We analysed human retina and brain samples from controls and donors with DM and/or AD. Immunofluorescence staining for NG2, PDGFRβ, and αSMA was performed to analyse pericyte marker expression, vascular staining coverage, and pericyte cellular density on capillaries. Results: In control retina and brain, the average pericyte staining coverage of capillaries was 70-80% based on NG2 and PDGFRβ expression, but only 25% when based on αSMA expression. Pericyte densities were 7 and 9 pericytes/mm capillary length in the control retina and brain, respectively. DM and DR retinas showed marked density reductions to 4 pericytes/mm capillary length. In DM without DR, retinal vascular staining coverage of NG2 and PDGFRβ decreased to 50-56%. In DR retinas, vascular coverage based on NG2 staining was comparable to controls, whereas coverage based on PDGFRβ staining was significantly reduced to 45%. Such reductions were not observed in brain samples from donors with DM or AD; however, NG2 staining was reduced in all patient groups. Both NG2 and PDGFRβ staining were markedly reduced in brain samples from donors with both DM and AD. Discussion: These trends suggest a specific pericyte pathology in the brain in cases of DM and AD, particularly in patients with both conditions, which differs from the well-characterized pericyte loss observed in the diabetic retina.