Immunoregulatory and amyloid-clearing phenotypes of conditional miR-155-depleted microglia in the retina of AD-model mice

Abstract

Purpose : A recent study in transgenic murine models of Alzheimer's disease (AD) described a unique microglial neurodegenerative phenotype (MGnD) that is triggered by amyloid-β plaque-mediated neuronal stress. The microRNA miR-155 was primarily characterized in relation to pro-inflammatory M1 microglia. However, recent research demonstrated regulatory role of miR-155 on neurodegenerative response in AD brain and its contribution to MGnD microglial phenotype differentiation. Our team identified the pathological hallmarks of AD in the neurosensory retina. We further found a tight correlation between the impacts of AD on brain and retinal pathology. Here, we sought to evaluate the roles of miR-155 depletion on microglial phenotypes associated with amyloidosis in the retina of transgenic murine models of AD.

Methods : The Cx3cr1-Cre^ERT2 mice were used to specifically and transiently target miR-155 depletion in microglia (miR-155^fl/fl) and were further introduced into APP_SWE/PS1_ΔE9 (ADtg) mice to generate Cx3cr1-Cre^ERT2:miR155^fl/fl:APP_SWE/PS1_ΔE9 mice. Oral treatment of tamoxifen was applied to induce miR-155 deletion at 2 months of age. At 4 and 8 months, mice were sacrificed to extract retinas for different experimental measurements. These, included inflammatory marker assessment by meso scale discovery (MSD) analysis, global proteomic profiles by mass spectrometry (MS), and microglial phenotypes associated with retinal abluminal and vascular amyloidosis by histological examination.

Results : Our initial results demonstrate that miR-155 deletion decreased expression of multiple cytokines including IFN-γ, TNFα, IL-2, IL-6 and IL-12 in the retinas of ADtg mice, as well as reduced TNF-α in wild type mice. Retinal cross section showed deposition of Aβ⁴² and Aβ⁴⁰ in retinal parenchyma and blood vessels in ADtg mice at 8 months. The miR-155 deletion in microglia seems to enhance clearance of retinal Aβ deposition in 8-month-old ADtg mice. Intriguingly, distinct retinal proteome profiles were identified in the Cx3cr1-Cre^ERT2:miR155^fl/fl:APP_SWE/PS1_ΔE9 mice.

Conclusions : Our data indicate that inhibiting miR-155 expression in CNS microglia may provide beneficial therapeutic effect in retinas of ADtg mice, including downregulating proinflammatory cytokines and enhanced Aβ clearance. These findings propose a potential new target for AD diagnosis and treatment.

This is a 2021 ARVO Annual Meeting abstract.