Regulating microglial miR-155 transcriptional phenotype alleviates Alzheimer's-induced retinal vasculopathy by limiting Clec7a/Galectin-3+ neurodegenerative microglia

Single cell RNA sequencing studies identified novel neurodegeneration-associated microglial (MGnD/DAM) subtypes activated around cerebral amyloid plaques. Micro-RNA (miR)-155 of the TREM2-APOE pathway was shown to be a key transcriptional regulator of MGnD microglial phenotype. Despite growing interest in studying manifestations of Alzheimer's disease (AD) in the retina, a CNS organ accessible to noninvasive high-resolution imaging, to date MGnD microglia have not been studied in the AD retina. Here, we discovered the presence and increased populations of Clec7a(+) and Galectin-3(+) MGnD microglia in retinas of transgenic APP(SWE)/PS1(L166P) AD-model mice. Conditionally targeting MGnD microglia by miR-155 ablation via the tamoxifen-inducible Cre(ERT2) system in APP(SWE)/PS1(L166P) mice diminished retinal Clec7a(+) and Galectin-3(+) microglial populations while increasing homeostatic P2ry12(+) microglia. Retinal MGnD microglia were often adhering to microvessels; their depletion protected the inner blood-retina barrier and reduced vascular amyloidosis. Microglial miR-155 depletion further limits retinal inflammation. Mass spectrometry analysis revealed enhanced retinal PI3K-Akt signaling and predicted IL-8 and Spp1 decreases in mice with microglia-specific miR-155 knockout. Overall, this study identified MGnD microglia in APP(SWE)/PS1(L166P) mouse retina. Transcriptional regulation of these dysfunctional microglia mitigated retinal inflammation and vasculopathy. The protective effects of microglial miR-155 ablation should shed light on potential treatments for retinal inflammation and vascular damage during AD and other ocular diseases.

Automated summary

This study identified the presence of MGnD microglia in the retina of AD-model mice and demonstrated their involvement in retinal inflammation and vascular damage. Transcriptional regulation of these microglia through miR-155 was found to play a key role in mitigating inflammation and protecting the blood-retina barrier.