OO083 - PROPAGATION OF AMYLOID PATHOLOGY BY CELL-DERIVED AΒ HEXAMERIC SEED (ID 1632)
Abstract
Aims
The formation of Aβ assemblies plays a crucial role in AD pathology. Our aim was to characterize pathological Aβ oligomers produced by cells and investigate their seeding properties and their contribution to amyloid pathology in a FAD mouse model.
Methods
Immunoprecipitation combined to mass spectrometry was used for the characterization of Aβ assemblies produced by cells expressing human APP amyloidogenic fragments (e.g C99 or βCTF). Nucleation properties of cell-derived Aβ assemblies were studied in vitro. Knock-down of Presenilin1/2 was performed to identify the type of γ-secretase involved in their production. Hexameric Aβ assemblies were isolated from cell cultures and further injected in FAD mice to study their pathological properties.
Results
Aβ hexamers were readily detectable in cell extracts and culture media of various cell lines expressing APP amyloidogenic fragments. Hexameric Aβ42 produced by cells displayed nucleating properties which are dependent on the availability of Aβ monomers. We found that Aβ hexamers were predominantly associated to PS2-dependent γ secretases. Hexameric-like Aβ assemblies were detected both in FAD mice brains and in the cerebrospinal fluid of AD patients. Finally, cell-derived hexameric Aβ was able to seed other human Aβ forms, resulting in the aggravation of amyloid deposition in FAD mice.
Conclusions
Aβ42 hexamers produced by cells have intrinsic nucleation features underlying their pathological properties. The PS2-dependent γ-secretase is critical for their production. They are present in FAD mice brains and human fluids, and their seeding properties aggravate the amyloid pathology in FAD mice.
