Streptozotocin Induces Alzheimer's Disease-Like Pathology in Hippocampal Neuronal Cells via CDK5/Drp1-Mediated Mitochondrial Fragmentation

Junghyung Park; Jinyoung Won; Jincheol Seo; Hyeon-Gu Yeo; Keonwoo Kim; Yu Gyeong Kim; Chang-Yeop Jeon; Min Kyoung Kam; Young-Hyun Kim; Jae-Won Huh; Sang-Rae Lee; Dong-Seok Lee; Youngjeon Lee

doi:10.3389/fncel.2020.00235

Streptozotocin Induces Alzheimer's Disease-Like Pathology in Hippocampal Neuronal Cells via CDK5/Drp1-Mediated Mitochondrial Fragmentation

Front Cell Neurosci. 2020 Aug 4:14:235. doi: 10.3389/fncel.2020.00235. eCollection 2020.

Authors

Junghyung Park¹, Jinyoung Won¹, Jincheol Seo¹, Hyeon-Gu Yeo^{1

2}, Keonwoo Kim^{1

3}, Yu Gyeong Kim^{1

2}, Chang-Yeop Jeon¹, Min Kyoung Kam³, Young-Hyun Kim^{1

2}, Jae-Won Huh^{1

2}, Sang-Rae Lee^{1

2}, Dong-Seok Lee³, Youngjeon Lee¹

Affiliations

¹ National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, South Korea.
² Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, South Korea.
³ School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, South Korea.

Abstract

Aberrant brain insulin signaling plays a critical role in the pathology of Alzheimer's disease (AD). Mitochondrial dysfunction plays a role in the progression of AD, with excessive mitochondrial fission in the hippocampus being one of the pathological mechanisms of AD. However, the molecular mechanisms underlying the progression of AD and mitochondrial fragmentation induced by aberrant brain insulin signaling in the hippocampal neurons are poorly understood. Therefore, we investigated the molecular mechanistic signaling associated with mitochondrial dynamics using streptozotocin (STZ), a diabetogenic compound, in the hippocampus cell line, HT-22 cells. In this metabolic dysfunctional cellular model, hallmarks of AD such as neuronal apoptosis, synaptic loss, and tau hyper-phosphorylation are induced by STZ. We found that in the mitochondrial fission protein Drp1, phosphorylation is increased in STZ-treated HT-22 cells. We also determined that inhibition of mitochondrial fragmentation suppresses STZ-induced AD-like pathology. Furthermore, we found that phosphorylation of Drp1 was induced by CDK5, and inhibition of CDK5 suppresses STZ-induced mitochondrial fragmentation and AD-like pathology. Therefore, these findings indicate that mitochondrial morphology and functional regulation may be a strategy of potential therapeutic for treating abnormal metabolic functions associated with the pathogenesis of AD.

Keywords: Alzheimer’s disease (AD); cyclin-dependent kinase 5 (CDK5); dynamin-1-like protein (Drp1); hippocampus; mitochondrial dynamics; streptozotocin (STZ).