Retinal vascular abnormalities and blood-retinal barrier breakdown in Alzheimer's disease.

Abstract

Vascular changes including cerebral amyloid angiopathy (CAA), reduced blood flow, pericyte loss and vascular platelet-derived growth factor receptor-β (PDGFRβ) deficiency have emerged as prominent features of Alzheimer's disease (AD). We previously identified the existence of the pathological hallmarks of AD, amyloid β-protein (Aβ) plaques, along with intracellular and vascular Aβ deposits in the neurosensory retina of AD patients. Data suggest that certain retinal signs manifest early in disease progression and appear similar to those observed in the brain. Yet, retinal vascular abnormalities in AD and their ability to predict cerebral pathology and cognitive decline are poorly understood. Here, we assessed vascular changes including capillary degeneration, PDGFRβ expression, vascular amyloidosis, pericyte loss, and blood-retinal barrier (BRB) permeability in postmortem retinas from a cohort of mild cognitively impaired (MCI) and AD patients. We evaluated retinal cross-sections from pre-defined topographical regions and isolated retinal vascular networks labeled by periodic acid-Schiff or immunofluorescence. We further quantified capillary degeneration, PDGFRβ expression, vascular amyloidosis, and inner BRB tight-junction molecule expression and BRB leakage in transgenic APPSWE /PS1ΔE9 mouse models of AD (ADtg mice) at different disease stages. Early and progressive PDGFRβ deficiency and pericyte loss were found in retinas from AD patients. PDGFRβ deficiency associated with vascular Aβ deposits in postmortem retinas from a cohort of MCI and AD patients. In ADtg mice as compared to age- and sex-matched wild-type mice, we found significant degeneration of retinal capillaries (P<0.0001). ADtg retinas also displayed a substantial vascular PDGFRβ deficiency (∼50% reduction, P=0.0017) and vascular Aβ deposition, which inversely correlated with the extent of degenerated capillaries (Pearson's r=-0.8, P=0.0016). Tight-junction alterations including claudin-1 downregulation and increased BRB permeability were found in ADtg mice. In postmortem retinas from the human cohort, retinal PDGFRβ loss significantly associated with increased retinal vascular Aβ40 and Aβ42 burdens. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were further revealed. Correlations were identified between retinal vascular abnormalities and cerebral Aβ burden, CAA, and clinical status. Overall, the identification of age- and Alzheimer's-dependent retinal capillary degeneration and compromised BRB integrity starting at early disease stages provide novel targets for AD diagnosis and therapy.