Effects of PSEN mutations on small molecules targeting the ??-secretase complex While investigations of FAD cases have provided invaluable insights into the pathogenesis of Calcitriol buy AD, patients with FAD further constitute a unique population to conduct treatment or prevention trials with novel pharmaceuticals. Consequently, international consortia aim to recruit FAD patients with PSEN mutations for future clinical trials. In the past, pharmaceutical companies have been cautious to include FAD patients in clinical trials with the argument that novel therapeutics might be less efficacious in these patients because of their specific genetic background or their more aggressive disease course. The described effects of PSEN mutations on small molecules targeting the ??-secretase complex, which constitutes a principal drug target in AD, have provided some support for this caution.

Initially, it was described that the efficacy of ??-secretase inhibitors to decrease A?? production was reduced in cultured cells overexpressing PSEN mutants [94-96]. Similarly, it was demonstrated that PSEN but not APP mutants blocked the effects of ??-secretase modulators (GSMs), which preferentially reduce the amyloidogenic A??42 species but spare proteolytic processing of the ??-secretase substrate NOTCH [94,97-100]. The initial studies used GSMs with low in vitro potency, which also did not have central nervous system drug properties. Recently, data have been reported for a second generation of potent and clinically relevant GSMs.

The overall interpretation of these studies is more complex, with one report showing that PSEN mutants reduced the ability of GSMs to lower A??42 irrespective of potency and structural class, and a second study claiming that only few particularly aggressive PSEN mutants rendered cells resistant to these GSMs [97,101]. It is important to note that all these results were obtained in cellular or animal models with overexpression of PSEN mutants. It remains possible, therefore, that the attenuating effect of PSEN mutants might not occur or be negligible when the mutation is expressed in the presence of one WT allele in FAD patients. A better understanding of presenilin mutations will require improved cellular models The lack of consensus concerning the effects Anacetrapib of PSEN FAD mutations on ??-secretase-dependent and -independent functions and the heterogeneity of results obtained for individual mutations clearly demonstrate that a better understanding of FAD PSEN mutations will require improved cellular models. These models need to account for the heterozygous expression of PSEN mutants in the presence of one WT allele in FAD patients, and they should allow a rigorous comparison www.selleckchem.com/products/kpt-330.html of the effects of a larger panel of mutations in a controlled system.