β-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity
Year: 2025
Type: article
Abstract: 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.
Source: Molecular Neurodegeneration
Authors: Brandon B. Holmes, Thaddeus K. Weigel, Jesseca M. Chung, Sarah K. Kaufman, Brandon I. Apresa, James R. Byrnes, Kaan S. Kumru, Jaime Vaquer-Alicea, Ankit Gupta, Indigo V. L. Rose, Yun Zhang, Alissa L. Nana, Dina Alter, Lea T. Grinberg, Salvatore Spina, Kevin K. Leung, Bruce L. Miller, Carlo Condello, Martin Kampmann, William W. Seeley, Jaeda C. Coutinho-Budd, James A. Wells
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,090
Funders: Shenandoah Community Foundation, Alzheimer's Association, BrightFocus Foundation, Sandler Foundation, National Institutes of Health, University of California, San Francisco, Brain Institute, University of Virginia, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Core Research for Evolutional Science and Technology
Awards: G1725061777, G1888650583, G1964544685, G2090380553, G3072607366, G3358765758, G60356126, G603598372, G683969282, Controlling Microglia States for Therapeutic Benefit in Alzheimer’s Disease, Relationships between conformational strains of tau and amyloid-beta, TREM2 and APOE variants, and phenotypic variations of Alzheimer's Disease, G7636448904, G816726602, G898313041, G9000006885, G9000029343, G9000060917, G9000064957, G9000148924, G9000167811, Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSP, Interrogating and Targeting Microglia Phagocytosis in Alzheimer’s Disease, Surfaceomic technologies and antibodies to probe cell surface proteomes and their interactomes at unprecedented small scale and high-resolution
OpenAlex ID: W4413836345