Peroxiredoxin 1 inhibits streptozotocin-induced Alzheimer’s disease-like pathology in hippocampal neuronal cells via Ca 2+ /Calpain/Cdk5-mediated mitochondrial fragmentation

Author:

Park Junghyung1,Won Jinyoung1,Yang Eunyeoung1,Seo Jincheol1,Cho Jiyeon1,Seong Jung Bae1,Yeo Hyeon-Gu1,Kim Keonwoo1,Kim Yu Gyeong1,Kim Minji1,Jeon Chang-Yeop1,Lim Kyung Seob1,Lee Dong-Seok2,Lee Youngjeon1

Affiliation:

1. Korea Research Institute of Bioscience and Biotechnology (KRIBB)

2. Kyungpook National University

Abstract

Abstract Oxidative stress plays an essential role in the progression of Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder. Streptozotocin (STZ)-induced abnormal brain insulin signaling and oxidative stress play crucial roles in the progression of Alzheimer’s disease (AD)-like pathology. Peroxiredoxins (Prxs) are associated with protection from neuronal death induced by oxidative stress. However, the molecular mechanisms underlying Prxs on STZ-induced progression of AD in the hippocampal neurons are not yet fully understood. Here, we investigated the effect of Peroxiredoxin 1 (Prx1) on STZ-induced AD-like pathology. Prx1 expression was increased by STZ treatment in the hippocampus cell line, HT-22 cells. We evaluated whether Prx1 affects STZ-induced HT-22 cells using overexpression. Prx1 successfully protected the forms of STZ-induced AD-like pathology, such as neuronal apoptosis, synaptic loss, and tau phosphorylation. Moreover, Prx1 suppressed STZ-induced increase of mitochondrial dysfunction and fragmentation by down-regulating Drp1 phosphorylation and mitochondrial location. Prx1 plays a role in an upstream signal pathway of Drp1 phosphorylation, cyclin-dependent kinase 5 (Cdk5) by inhibiting the STZ-induced conversion of p35 to p25. We found that STZ-induced of intracellular Ca2+ accumulation was an important modulator of AD-like pathology progression by regulating Ca2+-mediated Calpain activation, and Prx1 down-regulated STZ-induced intracellular Ca2+ accumulation and Ca2+-mediated Calpain activation. Finally, we identified that Prx1 antioxidant capacity affected Ca2+/Calpain/Cdk5-mediated AD-like pathology progress. Therefore, these findings demonstrated that Prx1 is a key factor in the STZ-induced hippocampal neuronal death through inhibition of Ca2+/Calpain/Cdk5-mediated mitochondrial dysfunction by protecting oxidative stress.

Publisher

Research Square Platform LLC

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