Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia
Neuron. 2021-05-01; 109(10): 1657-1674.e7
DOI: 10.1016/j.neuron.2021.03.024
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Wang C(1), Xiong M(1), Gratuze M(1), Bao X(1), Shi Y(1), Andhey PS(2), Manis M(1), Schroeder C(3), Yin Z(3), Madore C(3), Butovsky O(4), Artyomov M(2), Ulrich JD(5), Holtzman DM(6).
Author information:
(1)Department of Neurology, Hope Center for Neurological Disorders, Knight
Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110,
USA.
(2)Department of Pathology and Immunology, Washington University, St. Louis, MO
63110, USA.
(3)Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham
and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
(4)Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham
and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Evergrande
Center for Immunologic Diseases, Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA 02115, USA.
(5)Department of Neurology, Hope Center for Neurological Disorders, Knight
Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110,
USA. Electronic address: .
(6)Department of Neurology, Hope Center for Neurological Disorders, Knight
Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110,
USA. Electronic address: .
Comment in
Cell Rep Med. 2021 Jun 15;2(6):100316.
The apolipoprotein E (APOE) gene is the strongest genetic risk factor for
Alzheimer’s disease and directly influences tauopathy and tau-mediated
neurodegeneration. ApoE4 has strong deleterious effects on both parameters. In
the brain, apoE is produced and secreted primarily by astrocytes and by
activated microglia. The cell-specific role of each form of apoE in the setting
of neurodegeneration has not been determined. We generated P301S
Tau/Aldh1l1-CreERT2/apoE3flox/flox or Tau/Aldh1l1-CreERT2/apoE4flox/flox mice.
At 5.5 months of age, after the onset of tau pathology, we administered
tamoxifen or vehicle and compared mice at 9.5 months of age. Removing astrocytic
APOE4 markedly reduced tau-mediated neurodegeneration and decreased
phosphorylated tau (pTau) pathology. Single-nucleus RNA sequencing analysis
revealed striking gene expression changes in all cell types, with astrocytic
APOE4 removal decreasing disease-associated gene signatures in neurons,
oligodendrocytes, astrocytes, and microglia. Removal of astrocytic APOE4
decreased tau-induced synaptic loss and microglial phagocytosis of synaptic
elements, suggesting a key role for astrocytic apoE in synaptic degeneration.
Copyright © 2021 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neuron.2021.03.024
PMCID: PMC8141024
PMID: 33831349 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests D.M.H. is as an
inventor on a patent licensed by Washington University to C2N Diagnostics on the
therapeutic use of anti-tau antibodies. D.M.H. co-founded and is on the
scientific advisory board of C2N Diagnostics. C2N Diagnostics has licensed
certain anti-tau antibodies to AbbVie for therapeutic development. D.M.H. is on
the scientific advisory board of Denali and consults for Genentech, Merck, and
Cajal Neuroscience. All other authors declare no competing interests.