Increased Expression of PS1 Is Sufficient to Elevate the Level and Activity of γ-Secretase In Vivo

Increase in the generation and deposition of amyloid-beta (Ab) plays a central role in the development of Alzheimer's Disease (AD). Elevation of the activity of c-secretase, a key enzyme required for the generation for A beta, can thus be a potential risk factor in AD. However, it is not known whether gamma-secretase can be upregulated in vivo. While in vitro studies showed that expression of all four components of gamma-secretase (Nicastrin, Presenilin, Pen-2 and Aph-1) are required for upregulation of gamma-secretase, it remains to be established as to whether this is true in vivo. To investigate whether overexpressing a single component of the gamma-secretase complex is sufficient to elevate its level and activity in the brain, we analyzed transgenic mice expressing either wild type or familial AD (fAD) associated mutant PS1. In contrast to cell culture studies, overexpression of either wild type or mutant PS1 is sufficient to increase levels of Nicastrin and Pen-2, and elevate the level of active gamma-secretase complex, enzymatic activity of gamma-secretase and the deposition of A beta in brains of mice. Importantly, gamma-secretase comprised of mutant PS1 is less active than that of wild type PS1-containing gamma-secretase; however, gamma-secretase comprised of mutant PS1 cleaves at the A beta 42 site of APP-CTFs more efficiently than at the A beta 40 site, resulting in greater accumulation of A beta deposits in the brain. Our data suggest that whereas fAD-linked PS1 mutants cause early onset disease, upregulation of PS1/gamma-secretase activity may be a risk factor for late onset sporadic AD.