γ-secretase substrate concentration modulates the Aβ42/Aβ40 ratio

Mutation of the amyloid precursor protein (APP), presenilin 1, or presenilin-2 results in the development of early onset autosomal dominant forms of Alzheimer disease ( AD). These mutations lead to an increased A beta 42/A beta 40 ratio that correlates with the onset of disease. However, it remains unknown how these mutations affect gamma-secretase, a protease that generates the termini of A beta 40 and A beta 42. Here we have determined the reaction mechanism of gamma-secretase with wild type and three mutated APP substrates. Our findings indicate that despite the overall outcome of an increased A beta 42/A beta 40 ratio, these mutations each display rather distinct reactivity to gamma-secretase. Intriguingly, we found that the ratio of A beta 42/A beta 40 is variable with substrate concentration; increased substrate concentrations result in higher ratios of A beta 42/A beta 40. Moreover, we demonstrated that reduction of gamma-secretase substrate concentration by BACE1 inhibition in cells decreased the A beta 42/A beta 40 ratio. This study indicates that biological factors affecting targets such as BACE1 and APP, which ultimately cause an increased concentration of gamma-secretase substrate, can augment the A beta 42/A beta 40 ratio and may play a causative role in sporadic AD. Therefore, strategies lowering the A beta 42/A beta 40 ratio through partial reduction of gamma-secretase substrate production may introduce a practical therapeutic modality for treatment of AD.