2. Academic Validation
  3. APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints

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

  • Nat Immunol. 2023 Sep 25. doi: 10.1038/s41590-023-01627-6.
Zhuoran Yin # 1 2,  Neta Rosenzweig # 1,  Kilian L Kleemann 1 3,  Xiaoming Zhang 1,  Wesley Brandão 1,  Milica A Margeta 1 2,  Caitlin Schroeder 1,  Kisha N Sivanathan 1 4,  Sebastian Silveira 1,  Christian Gauthier 1,  Dania Mallah 1,  Kristen M Pitts 1 2,  Ana Durao 1,  Shawn Herron 5,  Hannah Shorey 1,  Yiran Cheng 1,  Jen-Li Barry 1,  Rajesh K Krishnan 1 4,  Sam Wakelin 1,  Jared Rhee 1,  Anthony Yung 1,  Michael Aronchik 1,  Chao Wang 6 7,  Nimansha Jain 6,  Xin Bao 6,  Emma Gerrits 8,  Nieske Brouwer 8,  Amy Deik 9,  Daniel G Tenen 10 11,  Tsuneya Ikezu 5 12,  Nicolas G Santander 13 14,  Gabriel L McKinsey 13,  Caroline Baufeld 1,  Dean Sheppard 15,  Susanne Krasemann 1 16,  Roni Nowarski 1 4,  Bart J L Eggen 8,  Clary Clish 9,  Rudolph E Tanzi 17,  Charlotte Madore 1 18,  Thomas D Arnold 13,  David M Holtzman 6,  Oleg Butovsky 19 20
Affiliations

Affiliations

  • 1 Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
  • 3 School of Computing, University of Portsmouth, Portsmouth, UK.
  • 4 Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
  • 6 Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
  • 7 Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, China.
  • 8 Department of Biomedical Sciences of Cells & Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • 9 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 10 Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA.
  • 11 Cancer Science Institute, National University of Singapore, Singapore, Singapore.
  • 12 Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
  • 13 Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
  • 14 Instituto de Ciencias de la Salud, Universidad de O´Higgins, Rancagua, Chile.
  • 15 Department of Medicine, Cardiovascular Research Center, University of California, San Francisco, San Francisco, CA, USA.
  • 16 Institute of Neuropathology, University Medical Center Hamburg-Eppendorf UKE, Hamburg, Germany.
  • 17 Genetics and Aging Research Unit, Massachusetts General Hospital, Boston, MA, USA.
  • 18 Laboratoire NutriNeuro, UMR1286, INRAE, Bordeaux INP, University of Bordeaux, Bordeaux, France.
  • 19 Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. obutovsky@bwh.harvard.edu.
  • 20 Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. obutovsky@bwh.harvard.edu.
  • # Contributed equally.
PMID: 37749326 DOI: 10.1038/s41590-023-01627-6
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.

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