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

Acta Neuropathol Commun. 2022 Sep 8;10(1):136. doi: 10.1186/s40478-022-01439-z.


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.

Keywords: Alzheimer’s disease; Inflammation; Microglia; Retinopathy; Vascular damage; microRNA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / metabolism
  • Animals
  • Disease Models, Animal
  • Galectin 3 / genetics
  • Galectin 3 / metabolism
  • Inflammation / metabolism
  • Lectins, C-Type / metabolism
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Transgenic
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Microglia / metabolism
  • Phenotype
  • Phosphatidylinositol 3-Kinases / genetics
  • Receptors, Immunologic / metabolism


  • Clec7a protein, mouse
  • Galectin 3
  • Lectins, C-Type
  • Membrane Glycoproteins
  • MicroRNAs
  • Mirn155 microRNA, mouse
  • Receptors, Immunologic
  • Trem2 protein, mouse