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  3. Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis

Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis

  • Immunity. 2024 Oct 9:S1074-7613(24)00458-8. doi: 10.1016/j.immuni.2024.09.014.
Seiji Kaji 1,  Stefan A Berghoff 2,  Lena Spieth 1,  Lennart Schlaphoff 1,  Andrew O Sasmita 3,  Simona Vitale 1,  Luca Büschgens 4,  Shreeya Kedia 1,  Martin Zirngibl 1,  Taisiia Nazarenko 1,  Alkmini Damkou 1,  Leon Hosang 5,  Constanze Depp 3,  Frits Kamp 6,  Patricia Scholz 7,  David Ewers 3,  Martin Giera 8,  Till Ischebeck 9,  Wolfgang Wurst 10,  Benedikt Wefers 10,  Martina Schifferer 11,  Michael Willem 12,  Klaus-Armin Nave 3,  Christian Haass 13,  Thomas Arzberger 14,  Sarah Jäkel 15,  Oliver Wirths 4,  Gesine Saher 3,  Mikael Simons 16
Affiliations

Affiliations

  • 1 Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  • 2 Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. Electronic address: stefan.berghoff@dzne.de.
  • 3 Max Planck Insitute for Multidisciplinary Sciences, Göttingen, Germany.
  • 4 Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany.
  • 5 Institute for Neuroimmunology and Multiple Sclerosis Research, Göttingen, Germany.
  • 6 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians University of Munich, Munich, Germany.
  • 7 Department of Plant Biochemistry, University of Goettingen, Albrecht-von-Haller-Institute for Plant Sciences, University of Göttingen, Göttingen, Germany.
  • 8 Leiden University Medical Center, Center for Proteomics and Metabolomics, Albinusdreef 2, 2333ZA Leiden, the Netherlands.
  • 9 Department of Plant Biochemistry, University of Goettingen, Albrecht-von-Haller-Institute for Plant Sciences, University of Göttingen, Göttingen, Germany; Institute of Plant Biology and Biotechnology (IBBP), Green Biotechnology, University of Münster, Münster, Germany.
  • 10 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Developmental Genetics, Neuherberg, Germany.
  • 11 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
  • 12 Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians University of Munich, Munich, Germany.
  • 13 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians University of Munich, Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
  • 14 Center for Neuropathology and Prion Research, Ludwig-Maximilians University of Munich, Munich, Germany; Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University Hospital, Munich, Germany.
  • 15 Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany.
  • 16 Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Munich, Germany; Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany. Electronic address: mikael.simons@dzne.de.
PMID: 39419029 DOI: 10.1016/j.immuni.2024.09.014
Abstract

The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer's disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (APOE) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with Amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.

Keywords

Alzheimer’s disease; ApoE; inflammation; lipids; microglia.

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