APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints
Nat Immunol. 2023-09-25; 24(11): 1839-1853
DOI: 10.1038/s41590-023-01627-6
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Yin Z(#)(1)(2), Rosenzweig N(#)(1), Kleemann KL(1)(3), Zhang X(1), Brandão W(1), Margeta MA(1)(2), Schroeder C(1), Sivanathan KN(1)(4), Silveira S(1), Gauthier C(1), Mallah D(1), Pitts KM(1)(2), Durao A(1), Herron S(5), Shorey H(1), Cheng Y(1), Barry JL(1), Krishnan RK(1)(4), Wakelin S(1), Rhee J(1), Yung A(1), Aronchik M(1), Wang C(6)(7), Jain N(6), Bao X(6), Gerrits E(8), Brouwer N(8), Deik A(9), Tenen DG(10)(11), Ikezu T(5)(12), Santander NG(13)(14), McKinsey GL(13), Baufeld C(1), Sheppard D(15), Krasemann S(1)(16), Nowarski R(1)(4), Eggen BJL(8), Clish C(9), Tanzi RE(17), Madore C(1)(18), Arnold TD(13), Holtzman DM(6), Butovsky O(19)(20).
Author information:
(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. .
(20)Evergrande Center for Immunologic Diseases, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA. .
(#)Contributed equally
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.
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41590-023-01627-6
PMID: 37749326 [Indexed for MEDLINE]