Oligomeric amyloid-β(1-42) induces THP-1 human monocyte adhesion and maturation

Amyloid-β (Aβ) is a naturally occurring 40- or 42-residue peptide fragment with a primary role in Alzheimer's disease (AD). Aggregated Aβ accumulates as both dense core plaques and diffuse deposits in the brains of AD patients. Aβ plaques are surrounded by activated microglia, some of which are believed to be derived from peripheral blood monocytes that have infiltrated the central nervous system and differentiated into phagocytes in response to Aβ. We have modeled this process using THP-1 human monocytes and found Aβ(1-42) to be as effective as phorbol myristate acetate at differentiating THP-1 monocytes based on cell adhesion, fibronectin binding, CD11b cell-surface expression, and morphological changes. Cell adhesion studies and atomic force microscopy imaging revealed an inverse correlation between Aβ(1-42)-induced monocyte maturation and aggregation progression. Freshly reconstituted Aβ(1-42) solutions were the most effective, yet continued aggregation reduced, and eventually abolished, the ability to induce monocyte adhesion. Aβ(1-40), lower aggregation concentrations of Aβ(1-42), and an aggregation-restricted Aβ(1-42) L34P mutant had little effect on monocyte adhesion under the same conditions as Aβ(1-42). These findings implicated an oligomeric, but not monomeric or fibrillar, Aβ(1-42) aggregation species in the monocyte maturation process. The rapidly-formed Aβ(1-42) oligomers were distinct from Aβ-derived diffusible ligands which did not elicit significant THP-1 monocyte adhesion. These data demonstrate that a specific oligomeric Aβ(1-42) aggregation species can potently initiate the THP-1 monocyte maturation process.