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Considering this promising evidence, we set up a study aimed to assess the effect of NPS 2143 in iPSC-neurons differentiated from a patient with familial AD carrying a genetic mutation in PSEN1. Indeed, we previously characterized iPSC-neurons derived from healthy individuals and from patients with sporadic and familial AD [16]. We found that AD neurons secreted higher levels of amyloid compared to healthy cultures, whereas a significantly higher Aβ42/Aβ40 ratio with respect to control cells was detected only in fAD neurons [16].

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Importantly, we next reported the beneficial effects of calcilytic in counteracting the pathomechanism of AD. We found that calcilytic reduced levels of Aβ40 and Aβ42 secreted from PSEN1 mutant neurons, while amyloid levels were not affected in the control cell lines. Such NPS 2143-mediated results reported only in fAD neurons would indicate that calcilytic can modulate Aβ levels only in the presence of an AD phenotype. In our fAD model, the increased Aβ42 secretion compared to the healthy counterpart could explain the selective effect of NPS 2143 obtained in these cells. Indeed, according to the hypothesized role of Aβ as an activator of the CaSR [35] and due to the higher presence of Aβ42 in the medium of fAD cells, the receptor of AD cultures might be more activated compared to the receptor of healthy cells, thus justifying the evident effect of NPS 2143 observed only in fAD neurons. In agreement, when NAHAs were treated with NPS 2143 alone, it did not modify the basal levels of the intracellular and the secreted amyloid Aβ42 [34]. Only when cells were exposed to synthetic Aβ, which caused a de novo production and release of amyloid, thus mimicking AD condition, addition of calcilytic was beneficial in counteracting the Aβ-mediated noxious effects [34]. In the indicated study, cells were treated with 20 μM synthetic fAβ25 - 35, an Aβ42 proxy, to induce an AD phenotype. Indeed, following this treatment, NAHAs displayed an augmented accumulation and secretion of Aβ42 while in parallel, cells presented higher intracellular amounts of Aβ40 and unchanged extracellular Aβ40 levels [34]. The authors found that co-treatment of fAβ25 - 35 with NPS 2143 fully abolished the Aβ42 intracellular accumulation and release. Instead, co-treatment of fAβ25 - 35 and calcilytic only partially decreased the Aβ-induced intracellular increase of Aβ40, while it promoted its secretion at the same time [34], which suggested that calcilytic differently modulates the secretion of Aβ40 and Aβ42 from fAβ25 - 35 exposed astrocytes. In contrast with this report, we found that NPS 2143 induced a similar reduction of both Aβ40 and Aβ42 species in the medium of our fAD cellular system. Considering that NPS 2143 modified the endogenously secreted amyloid levels of iPSC-derived neurons without any exogenous amyloid treatment, the effects exerted by the calcilytic might be physiologically relevant. 041b061a72