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

ABSTRACT: Substantial data indicate that amyloid-? (A?), 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 A?42 is a highly aggregating form of A?, the co-occurrence of shorter A? peptides might affect the aggregation potential of the A? pool. In this study we aimed to assess whether the structural behavior of human A?42 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 A? fragment impairs A?42 clearance through blood brain barrier and promotes the formation of A?42 aggregates even in the healthy brain. By showing that A?1-24 has seeding properties for aggregate formation in intracranially injected wild type mice, our study provide the proof-of-concept that peptides produced upon A?42 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.

SUBMITTER: Mazzitelli S 

PROVIDER: S-EPMC5057504 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature