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Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia.
Wang, Chao; Xiong, Monica; Gratuze, Maud; Bao, Xin; Shi, Yang; Andhey, Prabhakar Sairam; Manis, Melissa; Schroeder, Caitlin; Yin, Zhuoran; Madore, Charlotte; Butovsky, Oleg; Artyomov, Maxim; Ulrich, Jason D; Holtzman, David M.
Affiliation
  • Wang C; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA.
  • Xiong M; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA.
  • Gratuze M; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA.
  • Bao X; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA.
  • Shi Y; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA.
  • Andhey PS; Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
  • Manis M; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA.
  • Schroeder C; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Yin Z; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Madore C; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Butovsky O; 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.
  • Artyomov M; Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, USA.
  • Ulrich JD; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA. Electronic address: ulrichjd@wustl.edu.
  • Holtzman DM; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA. Electronic address: holtzman@wustl.edu.
Neuron ; 109(10): 1657-1674.e7, 2021 05 19.
Article in En | MEDLINE | ID: mdl-33831349
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phagocytosis / Astrocytes / Tauopathies / Apolipoprotein E4 Type of study: Risk_factors_studies Limits: Animals / Humans Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2021 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Phagocytosis / Astrocytes / Tauopathies / Apolipoprotein E4 Type of study: Risk_factors_studies Limits: Animals / Humans Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2021 Type: Article Affiliation country: United States