Secreted amyloid ?-proteins in a cell culture model include N-terminally extended peptides that impair synaptic plasticity.

ABSTRACT: Evidence for a central role of amyloid ?-protein (A?) in the genesis of Alzheimer’s disease (AD) has led to advanced human trials of A?-lowering agents. The “amyloid hypothesis” of AD postulates deleterious effects of small, soluble forms of A? on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble A? could be therapeutically advantageous, it is important to understand the full range of soluble A? derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ?8 kDa A? species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded A?40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of A?-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of A?. These N-terminally extended A?-containing monomeric fragments are distinct from soluble A? oligomers formed from A?1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing ?-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic A?-containing species can arise from APP processing events N-terminal to the classical ?-secretase cleavage site.

SUBMITTER: Welzel AT 

PROVIDER: S-EPMC4070750 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature