The DOI matches its Crossref record; 81 of the 81 references it cites were found in a registry or an index.
Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis
Open accessAbstract
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.
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“However, Aβ can bind to lipoproteins such as clusterin (ApoJ) and ApoE in the brain82–84, which facilitates its clearance by microglia via TREM281.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [81]
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“Although TREM2 has been shown to bind to Aβ and facilitate its uptake80,81, the surface expression changes of other receptors involved in Aβ recognition and uptake might have counteracted the effects of increased TREM2 signaling upon INPP5D haploinsufficiency83,84.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [81]
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“Microglia may also play a direct role in the fibrillization of Aβ through the uptake of Aβ bound to ApoE”
From Lipidome and proteome of astrocyte and microglia ApoE lipoprotein reveal differences based on cell type and ApoE isoform (2026) · cites this paper as [12]
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“Microglia have also been implicated in the initial fibrillization of Aβ, where ApoE and Aβ aggregates colocalize in lysosomes (12).”
From Lipidome and proteome of astrocyte and microglia ApoE lipoprotein reveal differences based on cell type and ApoE isoform (2026) · cites this paper as [12]
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“where both molecules aggregate in the endolysosomal pathway (12).”
From Lipidome and proteome of astrocyte and microglia ApoE lipoprotein reveal differences based on cell type and ApoE isoform (2026) · cites this paper as [12]
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Self-citationCRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens
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Wu, J., Ziyi, Z., Sun, Z., Yuan, S., & Qiu, L. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103347
LeeBae, J., Bopp, V., Goreth, A., Grozdanov, V., Engels, Z., Kühlwein, J. K., Gazzola, E., Rombach, D., Meier, L., Dimou, L., et al. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00046-9
Zhang, J., Zhou, H., Sun, F., Yang, P., Li, K., 管春香, He, J., Zhong, Z., Sun, S., Wu, Q., et al. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-03291-3
Strickland, M. R., & Holtzman, D. M. (2026) · Molecular Neurodegeneration · doi:10.1186/s13024-026-00970-0
Metadata
- Authors
- Kaji, S., Berghoff, S. A., Spieth, L., Schlaphoff, L., Sasmita, A. O., Vitale, S., Büschgens, L., Kedia, S., Zirngibl, M., Nazarenko, T., Damkou, A., Hosang, L., Depp, C., Kamp, F., Scholz, P., Ewers, D., Giera, M., Ischebeck, T., Wurst, W., Wefers, B., Schifferer, M., Willem, M., Nave, K.-A., Haass, C., Arzberger, T., Jäkel, S., Wirths, O., Saher, G., & Simons, M.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- Universitätsmedizin Göttingen (DE)
- University of Göttingen (DE)
- Leiden University Medical Center (NL)
- University of Münster (DE)
- Munich Cluster for Systems Neurology (DE)
- Ludwig-Maximilians-Universität München (DE)
- LMU Klinikum (DE)
- Institut für Schlaganfall- und Demenzforschung (DE)
- Corresponding author
- Berghoff, Stefan A.
- Simons, Mikael
- ORCID
- Kaji, Seiji
- Berghoff, Stefan A.
- Spieth, Lena
- Schlaphoff, Lennart
- Sasmita, Andrew O.
- Büschgens, Luca
- Kedia, Shreeya
- Zirngibl, Martin
- Damkou, Alkmini
- Depp, Constanze
- Kamp, Frits
- Scholz, Patricia
- Ewers, David
- Giera, Martin
- Ischebeck, Till
- Wurst, Wolfgang
- Wefers, Benedikt
- Schifferer, Martina
- Willem, Michael
- Nave, Klaus-Armin
- Haass, Christian
- Jäkel, Sarah
- Wirths, Oliver
- Saher, Gesine
- Simons, Mikael
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2024-11
- Volume
- 57
- Issue
- 11
- Pages
- 2651-2668.e12
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W4403455151
- Cited by
- 104
- References
- 81
- Citations by year
- 2026: 38 · 2025: 58 · 2024: 8
- FWCI
- 29.60
- Type
- journal article
- Language
- en
- Update notices
- erratum (2025-01-14)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunity (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- DZNE Pub (submittedVersion, cc-by)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Funders
- HORIZON EUROPE European Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- apolipoprotein E, protein aggregation, microglia, Alzheimer's disease, amyloid-beta, seeding, endolysosomal system, JAK/STAT signaling, endocytic uptake, amyloid plaques, HaloTag
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Humans, Mice, Transgenic, Signal Transduction, Amyloid beta-Peptides, Microglia, Lipid Metabolism, STAT Transcription Factors, Mice, Janus Kinases, Plaque, Amyloid, Protein Aggregation, Pathological
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