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

Autor: Haoshen Shi, Zhuoran Yin, Yosef Koronyo, Dieu-Trang Fuchs, Julia Sheyn, Miyah R. Davis, Jered W. Wilson, Milica A. Margeta, Kristen M. Pitts, Shawn Herron, Seiko Ikezu, Tsuneya Ikezu, Stuart L. Graham, Vivek K. Gupta, Keith L. Black, Mehdi Mirzaei, Oleg Butovsky, Maya Koronyo-Hamaoui
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Acta Neuropathologica Communications, Vol 10, Iss 1, Pp 1-22 (2022)
Druh dokumentu: article
ISSN: 2051-5960
DOI: 10.1186/s40478-022-01439-z
Popis: Abstract 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 APPSWE/PS1L166P AD-model mice. Conditionally targeting MGnD microglia by miR-155 ablation via the tamoxifen-inducible CreERT2 system in APPSWE/PS1L166P 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 APPSWE/PS1L166P 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.
Databáze: Directory of Open Access Journals
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