Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma

Milica A Margeta; Zhuoran Yin; Charlotte Madore; Kristen M Pitts; Sophia M Letcher; Jing Tang; Shuhong Jiang; Christian D Gauthier; Sebastian R Silveira; Caitlin M Schroeder; Eleonora M Lad; Alan Proia; Rudolph E Tanzi; David M Holtzman; Susanne Krasemann; Dong Feng Chen; Oleg Butovsky

doi:10.1016/j.immuni.2022.07.014

Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma

Milica A Margeta
, Zhuoran Yin
, Charlotte Madore
, Kristen M Pitts
, Sophia M Letcher
, Jing Tang
, Shuhong Jiang
, Christian D Gauthier
, Sebastian R Silveira
, Caitlin M Schroeder
, Eleonora M Lad
, Alan Proia
, Rudolph E Tanzi
, David M Holtzman
, Susanne Krasemann
, Dong Feng Chen
, Oleg Butovsky

Campbell University

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.
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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.
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.
Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA.
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.
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, USA.
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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: [email protected].

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	American English
Journal	Immunity
Volume	55
DOIs	https://doi.org/10.1016/j.immuni.2022.07.014
State	Published - Sep 13 2022

Keywords

APOE4
Alzheimer disease
Galectin-3
Lgals3
glaucoma
microglia
neurodegeneration
neuroprotection
retina

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Margeta, M. A., Yin, Z., Madore, C., Pitts, K. M., Letcher, S. M., Tang, J., Jiang, S., Gauthier, C. D., Silveira, S. R., Schroeder, C. M., Lad, E. M., Proia, A., Tanzi, R. E., Holtzman, D. M., Krasemann, S., Chen, D. F., & Butovsky, O. (2022). Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma. Immunity, 55. https://doi.org/10.1016/j.immuni.2022.07.014

Margeta, MA, Yin, Z, Madore, C, Pitts, KM, Letcher, SM, Tang, J, Jiang, S, Gauthier, CD, Silveira, SR, Schroeder, CM, Lad, EM, Proia, A, Tanzi, RE, Holtzman, DM, Krasemann, S, Chen, DF & Butovsky, O 2022, 'Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma', Immunity, vol. 55. https://doi.org/10.1016/j.immuni.2022.07.014

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title = "Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma",

abstract = " 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.",

keywords = "APOE4, Alzheimer disease, Galectin-3, Lgals3, glaucoma, microglia, neurodegeneration, neuroprotection, retina",

author = "Margeta, \{Milica A\} and Zhuoran Yin and Charlotte Madore and Pitts, \{Kristen M\} and Letcher, \{Sophia M\} and Jing Tang and Shuhong Jiang and Gauthier, \{Christian D\} and Silveira, \{Sebastian R\} and Schroeder, \{Caitlin M\} and Lad, \{Eleonora M\} and Alan Proia and Tanzi, \{Rudolph E\} and Holtzman, \{David M\} and Susanne Krasemann and Chen, \{Dong Feng\} and Oleg Butovsky",

year = "2022",

month = sep,

day = "13",

doi = "10.1016/j.immuni.2022.07.014",

language = "American English",

volume = "55",

journal = "Immunity",

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TY - JOUR

T1 - Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma

AU - Margeta, Milica A

AU - Yin, Zhuoran

AU - Madore, Charlotte

AU - Pitts, Kristen M

AU - Letcher, Sophia M

AU - Tang, Jing

AU - Jiang, Shuhong

AU - Gauthier, Christian D

AU - Silveira, Sebastian R

AU - Schroeder, Caitlin M

AU - Lad, Eleonora M

AU - Proia, Alan

AU - Tanzi, Rudolph E

AU - Holtzman, David M

AU - Krasemann, Susanne

AU - Chen, Dong Feng

AU - Butovsky, Oleg

PY - 2022/9/13

Y1 - 2022/9/13

N2 - 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.

AB - 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.

KW - APOE4

KW - Alzheimer disease

KW - Galectin-3

KW - Lgals3

KW - glaucoma

KW - microglia

KW - neurodegeneration

KW - neuroprotection

KW - retina

UR - https://cufind.campbell.edu/medicine_school/2414

U2 - 10.1016/j.immuni.2022.07.014

DO - 10.1016/j.immuni.2022.07.014

M3 - Article

VL - 55

JO - Immunity

JF - Immunity

ER -

Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma

Abstract

Keywords

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