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Updated: May 23, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
β-Amyloid Induces Microglial Expression of GPC4 and APOE Leading to Increased Neuronal Tau Pathology and Toxicity
Brandon B Holmes1,2, Thaddeus K Weigel3, Jesseca M Chung1
1Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Abstract:
To elucidate the impact of Aβ pathology on microglia in Alzheimer's disease pathogenesis, 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). In a Drosophila amyloidosis model, glial GPC4 expression exacerbates motor deficits and reduces lifespan, indicating that glial GPC4 contributes to a toxic cellular program during neurodegeneration. 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. These studies offer a mechanistic framework linking Aβ and tau pathology through microglial HSPGs and APOE.
Insights
Alzheimer's disease microglia upregulate Glypican 4 (GPC4), a heparan sulfate proteoglycan (HSPG), exacerbating neurodegeneration. GPC4 enhances microglia’s uptake of tau aggregates, with effects amplified by APOE.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) pathogenesis involves amyloid-beta (Aβ) and tau pathologies.
- Microglia, the brain's immune cells, play a critical role in AD progression.
- The microglial response to Aβ and its contribution to neurotoxicity are not fully understood.
Purpose of the Study:
- To investigate the impact of Aβ pathology on the microglia surfaceome.
- To identify specific molecules upregulated by microglia in response to Aβ.
- To elucidate the functional role of upregulated molecules in AD pathogenesis.
Main Methods:
- Microglia surfaceome profiling after Aβ fibril treatment.
- Drosophila amyloidosis model to assess glial GPC4 function.
- Cell culture experiments to evaluate GPC4's effect on microglia phagocytosis and neuronal tau uptake.
- Investigation of GPC4 interaction with APOE.
Main Results:
- Aβ-associated human microglia upregulate Glypican 4 (GPC4), a heparan sulfate proteoglycan (HSPG).
- Glial GPC4 expression in a Drosophila model worsens motor deficits and reduces lifespan.
- GPC4 enhances microglia phagocytosis of tau aggregates and facilitates neuronal tau uptake.
- GPC4-mediated effects are amplified by the presence of APOE.
Conclusions:
- Glial GPC4 contributes to a toxic cellular program during neurodegeneration.
- GPC4 links Aβ and tau pathology via microglial HSPGs and APOE.
- Targeting GPC4 may offer a therapeutic strategy for Alzheimer's disease.
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