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Haoshen Shi, Yosef Koronyo, Julia Sheyn, Dieu-Trang Fuchs, Keith Black, Maya Koronyo-Hamaoui; Degenerated Retinal Capillaries Associated with Vascular Amyloidosis in Murine Models of AD. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2252.
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© ARVO (1962-2015); The Authors (2016-present)
Recently, extensive effort has been invested into studying retinal pathology to improve early diagnosis and treatment of Alzheimer’s Disease (AD). Our group identified the pathological hallmarks of AD, Aβ plaques, including vascular amyloidosis in the retina. Although previous reports have broadly described retinal vascular-structural abnormalities in AD, little is known about the molecular pathways involved in AD pathogenesis. In the current study, we sought to evaluate retinal microvascular degeneration and pathways related to blood-retinal barrier (BRB) integrity in the double-transgenic APPSWE/PS1ΔE9 (AD+) mice model of AD.
AD+ mice and age- and sex-matched non-transgenic littermates (WT mice), ranging from 3 to 11 months of age, were sacrificed for biochemical and histopathological analysis. Retinal vessels were isolated to investigate degenerated capillaries and their correlation with vascular amyloidosis. ELISA and western blot were applied to retinal cryosections, and flatmounts were utilized to study retinal vascular tight junctions. The latter included ZO-1 and claudin-1, activation of NF-κB, PKCδ, and inflammatory cytokines. Fluorescein retinal imaging was applied to assess tight junction impairment and BRB permeability. These evaluations were correlated with brain pathology.
Our results show significant increases in the number of degenerated retinal capillaries in AD+ mice compared to WT mice. These trends were seen at the ages of 3 and 8 months, which became statistically significant at the average age of 11 months. Both 11-month-old AD+ and WT mice displayed more degenerated capillaries compared to the younger 8- and 3-month-old mice. In addition, both 4G8+Aβ plaques and 11A50+Aβ40-deposits in isolated retinal vasculature indicated substantial elevation of Aβ in retinal vessels of AD+ mice. A strong correlation was further discovered between retinal vascular amyloidosis and degenerated capillaries. Impairments in gap junction molecules and BRB permeability were also identified in pre- and post-symptomatic AD+ mice.
Our data indicate a compromised microvascular integrity and substantial increase in vascular amyloidosis in retinas of AD+ mice compared to WT mice, providing new, clinically important insights into vascular pathology in the AD retina.
This is a 2020 ARVO Annual Meeting abstract.
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