Amyloid-ß 1-24 C-terminal truncated fragment promotes amyloid-ß 1-42 aggregate formation in the healthy brain.

ABSTRACT

Substantial data indicate that amyloid-ß (Aß), the major component of senile plaques, plays a central role in Alzheimer's Disease and indeed the assembly of naturally occurring amyloid peptides into cytotoxic aggregates is linked to the disease pathogenesis. Although Aß42 is a highly aggregating form of Aß, the co-occurrence of shorter Aß peptides might affect the aggregation potential of the Aß pool. In this study we aimed to assess whether the structural behavior of human Aß42 peptide inside the brain is influenced by the concomitant presence of N-terminal fragments produced by the proteolytic activity of glial cells. We show that the occurrence of the human C-terminal truncated 1-24 Aß fragment impairs Aß42 clearance through blood brain barrier and promotes the formation of Aß42 aggregates even in the healthy brain. By showing that Aß1-24 has seeding properties for aggregate formation in intracranially injected wild type mice, our study provide the proof-of-concept that peptides produced upon Aß42 cleavage by activated glial cells may cause phenotypic defects even in the absence of genetic mutations associated with Alzheimer's Disease, possibly contributing to the development of the sporadic form of the pathology.