The presence of senile plaques in the brain is one of the pathological hallmarks of Alzheimer’s disease (AD).
The biogenesis and clearance of the amyloid β peptide (Aβ), the main component of the lesions, lie at the center of the
pathogenesis of AD. In sporadic AD, the increase of Aβ levels seems to be indicative of failure of clearance mechanisms.
We previously showed that the clearance of the wild type Aβ40 peptide by various neuronal and non-neuronal cells occurs
through a same proteolytic process and that Aβ degradation was primarily dictated by its conformational state (Panchal et
al., 2007). To gain further insights on the role of the peptide conformation in the clearance mechanism of Aβ, two Aβ40
peptides, known to be associated with amyloid angiopathy (Dutch and Flemish mutations), and the rodent Aβ40 peptide
were catabolized by several cells by using the same experimental approach. The peptide fragments, generated by proteolytic
cleavage of substrates in cell supernatants, were identified by LC-MS and the cleavage sites of proteases were deduced.
In parallel, conformational states of wild type Aβ40 peptide and of the three Aβ40 variants were characterized by
circular dichroism spectroscopy. We provide data suggesting that discrete conformational changes of Aβ40 peptide regulate
its clearance rate by neuronal and non-neuronal cells.