Phagocytes as plaque catalysts: Human macrophages generate seeding-competent Aβ42 fibrils with cross-seeding activity

Area of Science:

• Neuroimmunology
• Alzheimer's Disease Pathogenesis
• Protein Aggregation

Background:

• Microglia and macrophages are traditionally viewed as protective against amyloid beta (Aβ) in Alzheimer's disease (AD).
• Amyloid beta (Aβ) accumulation and aggregation into fibrils are central to AD pathology.
• The role of innate immune cells in initiating Aβ aggregation is not fully understood.

Purpose of the Study:

• To investigate the role of human phagocytic cells in producing extracellular amyloid beta (Aβ) fibrils.
• To characterize the seeding and tau cross-seeding potential of cell-generated Aβ42 fibrils.
• To explore the influence of AD risk genes, such as TREM2, on Aβ fibril formation.

Main Methods:

• Utilized differentiated THP-1 macrophages and human embryonic stem cell (hESC)-derived microglia.
• Analyzed extracellular Aβ42 fibril formation and seeding activity using biosensor models.
• Conducted transcriptomic profiling to identify cellular responses.
• Investigated the impact of TREM2 deficiency on Aβ fibrilogenesis.

Main Results:

• Human macrophages and microglia actively generate extracellular, seeding-competent Aβ42 fibrils.
• Cell-derived Aβ42 fibrils exhibit distinct structures and enhanced seeding/tau cross-seeding activity compared to synthetic fibrils.
• Aβ42 fibril formation requires active cellular processes and is increased upon loss of TREM2.
• Transcriptomic data revealed an early inflammatory response similar to AD-associated microglial states.

Conclusions:

• Challenges the paradigm of microglia/macrophages solely as guardians against Aβ in AD.
• Demonstrates that these immune cells can actively contribute to amyloid seeding.
• Highlights the potential dual role of microglia in AD pathogenesis: response and facilitation of amyloid assembly.
• Establishes a human-relevant in vitro model for studying Aβ aggregation and innate immunity in AD.