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, Vol. 24, No. 11, 11.2023, p. 1839-1853.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -