Phagocytes as Plaque Catalysts: Human Macrophages Actively Generate Pathogenic Aβ42 Fibrils with Seeding and...

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Microglia and macrophages are traditionally viewed as protective against amyloid beta (Aβ) in Alzheimer's disease (AD).
• The exact mechanisms by which these cells contribute to AD pathogenesis, particularly Aβ aggregation, remain incompletely understood.

Purpose of the Study:

• To investigate the role of human phagocytic cells, specifically macrophages and microglia, in the production of amyloid beta (Aβ) species.
• To characterize the structural and functional properties of cell-generated Aβ fibrils and their impact on tau pathology.
• To explore the influence of genetic factors, such as TREM2, on Aβ fibril formation.

Main Methods:

• Utilized differentiated THP-1 macrophages and induced pluripotent stem cell (iPSC)-derived microglia.
• Characterized extracellular Aβ42 fibrils using structural and functional assays.
• Performed transcriptomic profiling to analyze cellular responses.
• Investigated the effect of TREM2 gene knockout on Aβ fibril formation.

Main Results:

• Human macrophages and microglia actively produce extracellular, seeding-competent Aβ42 fibrils.
• Cell-generated Aβ fibrils exhibit enhanced seeding activity and can cross-seed tau aggregation.
• Aβ42 fibril formation requires active cellular processes and is increased upon loss of TREM2.
• Transcriptomic data revealed inflammatory responses similar to human AD models.

Conclusions:

• Macrophages and microglia play a dual role in AD, acting as both responders to and inadvertent catalysts of pathogenic amyloid formation.
• Cell-derived Aβ fibrils represent a novel pathogenic species with significant implications for AD progression and tau pathology.
• This human-relevant cellular system provides a platform for studying Aβ aggregation, innate immunity, and AD genetics, offering potential avenues for early therapeutic intervention.