Amyloid-β Production Via Cleavage of Amyloid-β Protein Precursor is Modulated by Cell Density

Mounting evidence suggests that Alzheimer's disease ( AD) is caused by the accumulation of the small peptide, amyloid-beta (A beta), a proteolytic cleavage product of amyloid-beta protein precursor (A beta PP). A beta is generated through a serial cleavage of A beta PP by beta- and gamma-secretase. A beta(40) and A beta(42) are the two main components of amyloid plaques in AD brains, with A beta(42) being more prone to aggregation. A beta PP can also be processed by alpha-secretase, which cleaves A beta PP within the A beta sequence, thereby preventing the generation of A beta. Little is currently known regarding the effects of cell density on A beta PP processing and A beta generation. Here we assessed the effects of cell density on A beta PP processing in neuronal and non-neuronal cell lines, as well as mouse primary cortical neurons. We found that decreased cell density significantly increases levels of A beta(40), A beta(42), total A beta, and the ratio of A beta(42): A beta(40). These results also indicate that cell density is a significant modulator of A beta PP processing. Overall, these findings carry profound implications for both previous and forthcoming studies aiming to assess the effects of various conditions and genetic/chemical factors, e.g., novel drugs on A beta PP processing and A beta generation in cell-based systems. Moreover, it is interesting to speculate whether cell density changes in vivo may also affect A beta PP processing and A beta levels in the AD brain.