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

Abstract Amyloid-beta (Aβ) deposits are one of the hallmarks of the neuropathological degeneration observed in Alzheimer's disease (AD) and Aβ concentrations have been reported to vary in different brain regions of AD patients. Aβ is produced by the sequential cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase, respectively. Previous studies have shown that over-expression of the γ-secretase complex leads to increased γ-secretase proteolytic activity increasing Aβ production. However, it is not known whether brain regions with highest Aβ concentration also express relatively higher levels of γ-secretase activity. Accordingly, the relationship between Aβ levels and γ-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 Aβ levels do vary in different brain regions in both transgenic and non-transgenic mice but are not correlated with regional γ-secretase activity. Furthermore, this study demonstrated that while mutations in the APP and PS1 sequences affect the absolute Aβ levels this is not reflected in an increase in γ-secretase proteolytic activity. The data in the current paper indicate that this assay is able to measure the level of γ-secretase activity in rodent species. Using this methodology will aid our understanding of physiological γ-secretase function.