A comparative assessment of γ-secretase activity in transgenic and non-transgenic rodent brain

Amyloid-beta (A beta) deposits are one of the hallmarks of the neuropathological degeneration observed in Alzheimer's disease (AD) and A beta concentrations have been reported to vary in different brain regions of AD patients. A beta is produced by the sequential cleavage of amyloid precursor protein (APP) by beta-secretase and gamma-secretase, respectively. Previous studies have shown that over-expression of the gamma-secretase complex leads to increased gamma-secretase proteolytic activity increasing A beta production. However, it is not known whether brain regions with highest A beta concentration also express relatively higher levels of gamma-secretase activity. Accordingly, the relationship between A beta levels and gamma-secretase activity across brain regions was investigated and correlated in the brains of transgenic and non-transgenic rodents commonly used in AD research. The data demonstrated that A beta levels do vary in different brain regions in both transgenic, and non-transgenic mice but are not correlated with regional gamma-secretase activity. Furthermore, this study demonstrated that while mutations in the APP and PSI sequences affect the absolute A beta levels this is not reflected in an increase in gamma-secretase proteolytic activity. The data in the current paper indicate that this assay is able to measure the level of gamma-secretase activity in rodent species. Using this methodology will aid our understanding of physiological gamma-secretase function. (c) 2006 Published by Elsevier B.V.