to a loss of function associated with the genetically heritable Familial Alzheimer’s disease (FAD) mutations [2]. Herein, the FAD mutations in PS1 are associated with a decrement in total amyloid levels [3] and a decrease in AICD production [4,5]. As noted, the loss in c-secretase proteolytic function may be mechanistically coupled with the increased production of the pathogenic Ab42 amyloid species [57]. Pathogenic amyloid production may induce ER stress [58,59], providing a mechanistic link between one of the cardinal features of AD and the manifestation of ER stress in AD patients. Deficits in proteolytic degradation and protein quality control observed in AD patients may promote protein aggregation [12], and subsequent ER stress induction, which could decrease c-secretase mediated processing of APP in sporadic AD patients. In this context, the disruption of de novo protein maturation and trafficking in the ER may promote stress and UPR activation, and replicate the loss of function component of AD pathogenesis. The capacity of PBA to counteract ER stress and promote protein trafficking through the secretory pathway, along with PBA mediated stimulation of a/c- cleavage, strongly supports the investigation into the therapeutic potential of PBA for the treatment of AD. Supporting Information Figure S1 APPGV16 localization shifts to intracellular organ- elles with thapsigargin, tunicamycin or brefeldin A treatment. NAG cells were grown on 4 well slides to approximately 80% confluence and remained untreated (top row), or were treated with 0.25 mg/mL thapsigargin (Thaps, second row), 5 mg/mL tunica- mycin (Tunic, third row), or 5 mg/mL brefeldin A (BFA, bottom References 1. Selkoe DJ, Podlisny MB (2002) Deciphering the genetic basis of Alzheimer’s disease. Annu Rev Genomics Hum Genet 3: 67–99. 2. 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In cells treated with thapsigargin or tunicamycin, the majority of APPGV16 was immediately adjacent to the nucleus, similar to the ER localization observed in the brefeldin A treated cells (BFA, bottom). Found at: doi:10.1371/journal.pone.0009135.s001 (11.11 MB TIF) Figure S2 ER stress induction represses c-secretase mediated cleavage of C99. The light bars represent N2a cells transfected with C99GV16 and the darker bars represent cells transfected with the c-secretase cleavage product C50GV16 (AICD fused to GV16). The single star (*) denotes a p-value,0.05; while the double star (**) denotes a p-value,0.001. All three stress inducing compounds inhibit C99GV16 cleavage; yet only thapsigargin and brefeldin A repress proteolysis to a statistically significant degree. None of the stress inducing compounds had any repressive effect upon C50GV16, demonstrating that stress induction does not impair the function of the genetic reporter system. 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