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APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints

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APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints. / Yin, Zhuoran; Rosenzweig, Neta; Kleemann, Kilian L; Zhang, Xiaoming; Brandão, Wesley; Margeta, Milica A; Schroeder, Caitlin; Sivanathan, Kisha N; Silveira, Sebastian; Gauthier, Christian; Mallah, Dania; Pitts, Kristen M; Durao, Ana; Herron, Shawn; Shorey, Hannah; Cheng, Yiran; Barry, Jen-Li; Krishnan, Rajesh K; Wakelin, Sam; Rhee, Jared; Yung, Anthony; Aronchik, Michael; Wang, Chao; Jain, Nimansha; Bao, Xin; Gerrits, Emma; Brouwer, Nieske; Deik, Amy; Tenen, Daniel G; Ikezu, Tsuneya; Santander, Nicolas G; McKinsey, Gabriel L; Baufeld, Caroline; Sheppard, Dean; Krasemann, Susanne; Nowarski, Roni; Eggen, Bart J L; Clish, Clary; Tanzi, Rudolph E; Madore, Charlotte; Arnold, Thomas D; Holtzman, David M; Butovsky, Oleg.

in: NAT IMMUNOL, Jahrgang 24, Nr. 11, 11.2023, S. 1839-1853.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Yin, Z, Rosenzweig, N, Kleemann, KL, Zhang, X, Brandão, W, Margeta, MA, Schroeder, C, Sivanathan, KN, Silveira, S, Gauthier, C, Mallah, D, Pitts, KM, Durao, A, Herron, S, Shorey, H, Cheng, Y, Barry, J-L, Krishnan, RK, Wakelin, S, Rhee, J, Yung, A, Aronchik, M, Wang, C, Jain, N, Bao, X, Gerrits, E, Brouwer, N, Deik, A, Tenen, DG, Ikezu, T, Santander, NG, McKinsey, GL, Baufeld, C, Sheppard, D, Krasemann, S, Nowarski, R, Eggen, BJL, Clish, C, Tanzi, RE, Madore, C, Arnold, TD, Holtzman, DM & Butovsky, O 2023, 'APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints', NAT IMMUNOL, Jg. 24, Nr. 11, S. 1839-1853. https://doi.org/10.1038/s41590-023-01627-6

APA

Yin, Z., Rosenzweig, N., Kleemann, K. L., Zhang, X., Brandão, W., Margeta, M. A., Schroeder, C., Sivanathan, K. N., Silveira, S., Gauthier, C., Mallah, D., Pitts, K. M., Durao, A., Herron, S., Shorey, H., Cheng, Y., Barry, J-L., Krishnan, R. K., Wakelin, S., ... Butovsky, O. (2023). APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints. NAT IMMUNOL, 24(11), 1839-1853. https://doi.org/10.1038/s41590-023-01627-6

Vancouver

Yin Z, Rosenzweig N, Kleemann KL, Zhang X, Brandão W, Margeta MA et al. APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints. NAT IMMUNOL. 2023 Nov;24(11):1839-1853. https://doi.org/10.1038/s41590-023-01627-6

Bibtex

@article{fc4ea89875df455ebb2aa7aa4ab01be3,
title = "APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints",
abstract = "The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD-astrocyte cross-talk associated with β-amyloid (Aβ) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8-transforming growth factor-β (TGFβ) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD-astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4-ITGB8-TGFβ pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8-TGFβ signaling provides a promising therapeutic intervention for AD.",
keywords = "Female, Mice, Humans, Animals, Alzheimer Disease/genetics, Apolipoprotein E4/genetics, Microglia/metabolism, Galectin 3/genetics, Amyloid beta-Peptides/metabolism, Mice, Transgenic, Disease Models, Animal",
author = "Zhuoran Yin and Neta Rosenzweig and Kleemann, {Kilian L} and Xiaoming Zhang and Wesley Brand{\~a}o and Margeta, {Milica A} and Caitlin Schroeder and Sivanathan, {Kisha N} and Sebastian Silveira and Christian Gauthier and Dania Mallah and Pitts, {Kristen M} and Ana Durao and Shawn Herron and Hannah Shorey and Yiran Cheng and Jen-Li Barry and Krishnan, {Rajesh K} and Sam Wakelin and Jared Rhee and Anthony Yung and Michael Aronchik and Chao Wang and Nimansha Jain and Xin Bao and Emma Gerrits and Nieske Brouwer and Amy Deik and Tenen, {Daniel G} and Tsuneya Ikezu and Santander, {Nicolas G} and McKinsey, {Gabriel L} and Caroline Baufeld and Dean Sheppard and Susanne Krasemann and Roni Nowarski and Eggen, {Bart J L} and Clary Clish and Tanzi, {Rudolph E} and Charlotte Madore and Arnold, {Thomas D} and Holtzman, {David M} and Oleg Butovsky",
note = "{\textcopyright} 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2023",
month = nov,
doi = "10.1038/s41590-023-01627-6",
language = "English",
volume = "24",
pages = "1839--1853",
journal = "NAT IMMUNOL",
issn = "1529-2908",
publisher = "NATURE PUBLISHING GROUP",
number = "11",

}

RIS

TY - JOUR

T1 - APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints

AU - Yin, Zhuoran

AU - Rosenzweig, Neta

AU - Kleemann, Kilian L

AU - Zhang, Xiaoming

AU - Brandão, Wesley

AU - Margeta, Milica A

AU - Schroeder, Caitlin

AU - Sivanathan, Kisha N

AU - Silveira, Sebastian

AU - Gauthier, Christian

AU - Mallah, Dania

AU - Pitts, Kristen M

AU - Durao, Ana

AU - Herron, Shawn

AU - Shorey, Hannah

AU - Cheng, Yiran

AU - Barry, Jen-Li

AU - Krishnan, Rajesh K

AU - Wakelin, Sam

AU - Rhee, Jared

AU - Yung, Anthony

AU - Aronchik, Michael

AU - Wang, Chao

AU - Jain, Nimansha

AU - Bao, Xin

AU - Gerrits, Emma

AU - Brouwer, Nieske

AU - Deik, Amy

AU - Tenen, Daniel G

AU - Ikezu, Tsuneya

AU - Santander, Nicolas G

AU - McKinsey, Gabriel L

AU - Baufeld, Caroline

AU - Sheppard, Dean

AU - Krasemann, Susanne

AU - Nowarski, Roni

AU - Eggen, Bart J L

AU - Clish, Clary

AU - Tanzi, Rudolph E

AU - Madore, Charlotte

AU - Arnold, Thomas D

AU - Holtzman, David M

AU - Butovsky, Oleg

N1 - © 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2023/11

Y1 - 2023/11

N2 - The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD-astrocyte cross-talk associated with β-amyloid (Aβ) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8-transforming growth factor-β (TGFβ) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD-astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4-ITGB8-TGFβ pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8-TGFβ signaling provides a promising therapeutic intervention for AD.

AB - The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD-astrocyte cross-talk associated with β-amyloid (Aβ) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8-transforming growth factor-β (TGFβ) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD-astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4-ITGB8-TGFβ pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8-TGFβ signaling provides a promising therapeutic intervention for AD.

KW - Female

KW - Mice

KW - Humans

KW - Animals

KW - Alzheimer Disease/genetics

KW - Apolipoprotein E4/genetics

KW - Microglia/metabolism

KW - Galectin 3/genetics

KW - Amyloid beta-Peptides/metabolism

KW - Mice, Transgenic

KW - Disease Models, Animal

U2 - 10.1038/s41590-023-01627-6

DO - 10.1038/s41590-023-01627-6

M3 - SCORING: Journal article

C2 - 37749326

VL - 24

SP - 1839

EP - 1853

JO - NAT IMMUNOL

JF - NAT IMMUNOL

SN - 1529-2908

IS - 11

ER -