First, public cell line repositories do not contain primary cells with a sufficient number of different PSEN mutations, and it is at present virtually impossible Fluoro-Sorafenib to acquire cells for specific mutations. Second, a general problem is the lack of genetically matched control cell lines. Commonly, cell lines derived from healthy donors are used as controls, which, because of differences in genetic background and cell derivation, display considerable biological variability. This concern could be addressed in the future through novel methods of genome editing, such as engineered zinc finger nucleases that might allow the generation of isogenic control cell lines [103]. However, these methods are not yet efficient enough to produce adequate numbers of mutant cell lines.

Third, even if genetically matched control cells are available, the biological variability between mutant cell lines derived from donors with different PSEN FAD mutations makes them likely unsuitable for stringently controlled biochemical experiments. However, a clear alternative to human patient-derived cell lines are mouse embryonic stem cells, which are more easily amendable to genome editing using sitespecific recombinases [104]. Evidently, to establish improved models that faithfully reproduce the genetic and biochemical characteristics of PSEN FAD patients will be laborious and time-consuming, but it is clearly required to overcome the shortcomings of current models based on overexpression of PSEN mutants. Conclusion APP and PSEN mutations cause FAD with autosomaldominant inheritance and early onset disease.

FAD is clinically and neuropathologically largely indistinguishable from the sporadic forms of AD, indicating that amyloidosis is a driving force in the etiology of both FAD and sporadic AD. Biochemical studies have shown that APP mutations either shift the generation of A?? peptides towards the highly amyloidogenic A??42 isoform or enhance the aggregation propensity of the A?? peptides. No evidence has been found that these mutations impair the physiological function of APP. PSEN mutations also drive amyloidosis in FAD patients through changes in the A??42/A??40 ratio. In addition, it has been proposed that PSEN mutations could impair other ??-secretase-dependent and -independent functions of PSEN. It is Anacetrapib important, however, to note that none of theses phenotypes have been comprehensively replicated in experimental models that bear relevance to the heterozygous genetic background of FAD patients with PSEN mutations. In the few studies that have used primary cells from FAD patients or heterozygous inhibitor Nutlin-3a knock-in mice, only single or a small number of PSEN mutations were investigated.