Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma
Immunity. 2022-09-01; 55(9): 1627-1644.e7
DOI: 10.1016/j.immuni.2022.07.014
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Margeta MA(1), Yin Z(2), Madore C(3), Pitts KM(1), Letcher SM(1), Tang J(4), Jiang S(5), Gauthier CD(2), Silveira SR(2), Schroeder CM(2), Lad EM(6), Proia AD(7), Tanzi RE(8), Holtzman DM(9), Krasemann S(10), Chen DF(5), Butovsky O(11).
Author information:
(1)Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham
and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Department of
Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School,
Boston, MA, USA.
(2)Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham
and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
(3)Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham
and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Univ. Bordeaux,
INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux, France.
(4)Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of
Ophthalmology, Harvard Medical School, Boston, MA, USA; Department of
Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.
(5)Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of
Ophthalmology, Harvard Medical School, Boston, MA, USA.
(6)Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA.
(7)Department of Pathology, Duke University Medical Center, Durham, NC, USA;
Department of Pathology, Campbell University School of Osteopathic Medicine,
Lillington, NC, USA.
(8)Genetics and Aging Research Unit, McCance Center for Brain Health, Mass
General Institute for Neurodegenerative Disease, Department of Neurology,
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
(9)Department of Neurology, Hope Center for Neurological Disorders, Knight
Alzheimer Disease Research Center, Washington University, St. Louis, MO, USA.
(10)Institute of Neuropathology, University Medical Center Hamburg-Eppendorf,
Hamburg, Germany.
(11)Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham
and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Evergrande Center
for Immunologic Diseases, Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA, USA. Electronic address: .
The apolipoprotein E4 (APOE4) allele is associated with an increased risk of
Alzheimer disease and a decreased risk of glaucoma, but the underlying
mechanisms remain poorly understood. Here, we found that in two mouse glaucoma
models, microglia transitioned to a neurodegenerative phenotype characterized by
upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in
human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or
carrying the human APOE4 allele were protected from retinal ganglion cell (RGC)
loss, despite elevated intraocular pressure (IOP). Similarly to Apoe-/- retinal
microglia, APOE4-expressing microglia did not upregulate
neurodegeneration-associated genes, including Lgals3, following IOP elevation.
Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration,
and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These
results demonstrate that impaired activation of APOE4 microglia is protective in
glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this
blinding disease.
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