β-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity
To define how Aβ pathology alters microglia function in Alzheimer’s disease, we profiled the microglia surfaceome following treatment with Aβ fibrils. Our findings reveal that Aβ-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). Glial GPC4 expression exacerbates motor deficits and reduces lifespan in a Drosophila amyloidosis model, implicating GPC4 in a toxic neurodegenerative program. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. In human Alzheimer’s disease brain, microglial GPC4 expression surrounding Aβ plaques correlates with neuritic tau pathology, supporting a pathological link between amyloid, GPC4, and tau. These studies define a mechanistic pathway by which Aβ primes microglia to promote tau pathology via HSPGs and APOE.
Authors
- Lea T. Grinberg (ORCID: https://orcid.org/0000-0002-6809-0618)
- Indigo V.L. Rose (ORCID: https://orcid.org/0000-0003-0491-1269)
- Brandon B. Holmes (ORCID: https://orcid.org/0000-0002-1153-840X)
- Alissa L. Nana (ORCID: https://orcid.org/0000-0003-3474-8044)
- Jaime Vaquer‐Alicea (ORCID: https://orcid.org/0000-0001-8363-9579)
- Salvatore Spina (ORCID: https://orcid.org/0000-0003-3570-9143)
- Thaddeus K. Weigel (ORCID: https://orcid.org/0000-0003-1698-3438)
- Jaeda Coutinho‐Budd (ORCID: https://orcid.org/0000-0002-7055-5701)
- Bruce L. Miller (ORCID: https://orcid.org/0000-0002-2152-4220)
- James A. Wells (ORCID: https://orcid.org/0000-0001-8267-5519)
- Kevin Leung (ORCID: https://orcid.org/0000-0002-2087-4974)
- Martin Kampmann (ORCID: https://orcid.org/0000-0002-3819-7019)
- Jon Chung (ORCID: https://orcid.org/0000-0003-0526-3670)
- James R. Byrnes (ORCID: https://orcid.org/0000-0003-0297-1209)
- Sarah K. Kaufman
- Kaan S. Kumru (ORCID: https://orcid.org/0000-0002-8015-0775)
- Carlo Condello (ORCID: https://orcid.org/0000-0002-8454-5360)
- Yun Zhang (ORCID: https://orcid.org/0000-0001-7242-1224)
- Ankit Gupta (ORCID: https://orcid.org/0000-0001-5295-180X)
- William W. Seeley
- Dina Alter
- Brandon I. Apresa
Institutions
- University of California, San Francisco (US)
- Institute for Neurodegenerative Disorders (US)
- University of Virginia (US)
- University of San Francisco (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Molecular Neurodegeneration
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1186/s13024-025-00883-4
- Citations
- 2
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.33
Funders
- Alzheimer's Association
- BrightFocus Foundation
- Sandler Foundation
- National Institutes of Health
- University of California, San Francisco
- Brain Institute, University of Virginia
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke
- Core Research for Evolutional Science and Technology