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Protease nexin-1 protects against Alzheimer’s disease by regulating the sonic hedgehog signaling pathway

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Abstract Objective To explore the role of protease nexin-1 (PN-1) in Alzheimer’s disease (AD) via the sonic hedgehog (SHH) pathway. Methods PN-1 lentiviral activation particles were injected into APP/PS1 transgenic… Click to show full abstract

Abstract Objective To explore the role of protease nexin-1 (PN-1) in Alzheimer’s disease (AD) via the sonic hedgehog (SHH) pathway. Methods PN-1 lentiviral activation particles were injected into APP/PS1 transgenic AD and wild-type (WT) mice; these mice were subjected to the Morris water maze test, followed by ELISA, thioflavin S staining and NeuN-TUNEL dual staining. HT22 cells were induced with Aβ1–42 and treated with PN-1 siRNA and/or cyclopamine (an SHH signaling inhibitor). The cells were then subjected to MTT and Annexin V-FITC/PI analyses. qRT-PCR and Western blotting were conducted to measure mRNA and protein expression. Results The escape latency of the APP/PS1 transgenic AD mice was extended with a decreased number of platform crossings; in addition, increased Aβ deposits, Aβ1–42 levels and hippocampal neuron apoptosis were observed in the brain tissues of AD mice. However, these changes were improved by PN-1 lentiviral activation particles. In addition, PN-1 overexpression inhibited the SHH pathway in AD mice. Moreover, PN-1 overexpression abolished the Aβ1–42-induced activation of the SHH pathway in HT22 cells. In addition, Aβ1–42 induction resulted in an increased apoptotic rate and decreased cell viability of HT22 cells; however, these effects were reversed by PN-1 or cyclopamine. Compared with that in the PN-1 siRNA + cyclopamine + Aβ1–42 group, apoptosis of HT22 cells in the cyclopamine + Aβ1–42 group was reduced and cell viability was improved. Conclusion PN-1, by blocking SHH pathway, reduced apoptosis of hippocampal neurons to improve spatial learning and memory ability, thereby playing a protective role in AD.

Keywords: alzheimer disease; ht22 cells; protease nexin; shh pathway; sonic hedgehog

Journal Title: International Journal of Neuroscience
Year Published: 2020

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