@article{5a5fda38df224080a90bd0774c7be92e,
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 Proia, {Alan D.} and Tanzi, {Rudolph E.} and Holtzman, {David M.} and Susanne Krasemann and Chen, {Dong Feng} and Oleg Butovsky",
note = "Funding Information: This study was supported by the Cure Alzheimer's Fund (to O.B. and D.M.H.); BrightFocus Foundation 2020A016806 (O.B.); NIH/NINDS R01 NS088137 (O.B.), NIH/NIA R01 AG051812 (O.B.) and R01 AG054672 (O.B.); NIH/NEI R01 EY027921 (O.B.); and NIH/NEI K12 EY016335 (M.A.M.), NIH/NEI K08 EY030160 (M.A.M.), American Glaucoma Society Young Clinician Scientist Award (M.A.M.), Research to Prevent Blindness Career Development Award (M.A.M.), Robert M. Sinskey Foundation (M.A.M.), Ruettgers Family Charitable Foundation (M.A.M.), and B.L. Manger Foundations (M.A.M.). Additional funding: R01 GM132668 (O.B.); R01 AG075509 (O.B.); R21 NS104609 (O.B.) and R21 NS101673 (O.B.); National Multiple Sclerosis Society ( 5092A1 ) (O.B.); National Health and Medical Research Council Australia ( RG180378 ) (O.B.); Nancy Davis Foundation innovative Award (O.B.); Amyotrophic Lateral Sclerosis Association Award (O.B.); NIH/NEI EY025913 (D.F.C.) and NIH/NEI EY025259 (D.F.C.); Massachusetts Eye and Ear Summit Fund (D.F.C.); NIH/NEI 5K23EY026988 (E.M.L.); Research to Prevent Blindness Ernest & Elizabeth Althouse Special Scholar Award (E.M.L.); and Core Grant for Vision Research from NIH/NEI to the Schepens Eye Research Institute ( P30EY03790 ). We thank Lai Ding and the NeuroTechnology Studio at BWH for providing confocal instrument access and consultation on data acquisition and analysis and the UMIF/UKE Hamburg for access to the SP5 confocal microscope. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = sep,
day = "13",
doi = "10.1016/j.immuni.2022.07.014",
language = "English",
volume = "55",
pages = "1627--1644.e7",
journal = "Immunity",
issn = "1074-7613",
number = "9",
}