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

Park, Junghyung; Won, Jinyoung; Seo, Ji Hun; Yeo, Hyeon-Gu; Kim, Keon-Woo; Kim, Yu Gyeong; Jeon, Chang‐Yeop; Kam, Min Kyoung; Kim, Younghyun; Huh, Jae‐Won; Lee, Sang-Rae; Lee, Dong‐Seok; Lee, Youngjeon

doi:10.3389/fncel.2020.00235

Cited by 28 publications

(34 citation statements)

References 74 publications

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“…Excess mitochondrial fission resulting from increased Drp1 levels can disturb the delicate balance between mitochondrial fission and fusion events, promote mitochondrial fragmentation and ultimately compromise mitochondrial functionality [16,17,[40][41][42][43][44][45]. Additionally, Drp1-driven mitochondrial fragmentation can undermine mitochondrial respiration, alter calcium storage, and lead to increased ROS production [40,43]. Another study reported that changes due to increased Drp1-mediated mitochondrial fragmentation impair metabolic functions, which compromises mitochondrial homeostasis in neuroinflammation [44].…”

Section: Discussionmentioning

confidence: 99%

Reduced Levels of Drp1 Protect against Development of Retinal Vascular Lesions in Diabetic Retinopathy

Kim

Sesaki

Roy

2021

Cells

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High glucose (HG)-induced Drp1 overexpression contributes to mitochondrial dysfunction and promotes apoptosis in retinal endothelial cells. However, it is unknown whether inhibiting Drp1 overexpression protects against the development of retinal vascular cell loss in diabetes. To investigate whether reduced Drp1 level is protective against diabetes-induced retinal vascular lesions, four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Drp1+/− mice, and STZ-induced diabetic Drp1+/− mice were examined after 16 weeks of diabetes. Western Blot analysis indicated a significant increase in Drp1 expression in the diabetic retinas compared to those of WT mice; retinas of diabetic Drp1+/− mice showed reduced Drp1 level compared to those of diabetic mice. A significant increase in the number of acellular capillaries (AC) and pericyte loss (PL) was observed in the retinas of diabetic mice compared to those of the WT control mice. Importantly, a significant decrease in the number of AC and PL was observed in retinas of diabetic Drp1+/− mice compared to those of diabetic mice concomitant with increased expression of pro-apoptotic genes, Bax, cleaved PARP, and increased cleaved caspase-3 activity. Preventing diabetes-induced Drp1 overexpression may have protective effects against the development of vascular lesions, characteristic of diabetic retinopathy.

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Section: Discussionmentioning

confidence: 99%

Reduced Levels of Drp1 Protect against Development of Retinal Vascular Lesions in Diabetic Retinopathy

Kim

Sesaki

Roy

2021

Cells

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“…As such, imbalanced fusion/fission leads to mitochondrial dysfunction and degeneration. Emerging evidence links Cdk5 hyperactivity to excessive mitochondrial fission under pathological conditions, such as neurotoxic insults and neurodegenerative diseases [120][121][122][123][124][125][126][127].…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

“…Drp1 is recruited from the cytosol to the mitochondrial outer membrane (MOM), where it assembles into ring-like structures that wrap around the MOM and incise the membrane following GTP hydrolysis [118]. In pathological conditions, Cdk5 phosphorylates Drp1 at S616, which increases its mitochondrial translocalization and GTPase activity, ultimately accelerating mitochondrial fission [120][121][122][123][124][125][126][127]. Excessive mitochondrial fission is associated with mitochondrial defects and neuronal death.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Three decades of Cdk5

Pao

Tsai

2021

J Biomed Sci

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Cdk5 is a proline-directed serine/threonine protein kinase that governs a variety of cellular processes in neurons, the dysregulation of which compromises normal brain function. The mechanisms underlying the modulation of Cdk5, its modes of action, and its effects on the nervous system have been a great focus in the field for nearly three decades. In this review, we provide an overview of the discovery and regulation of Cdk5, highlighting recent findings revealing its role in neuronal/synaptic functions, circadian clocks, DNA damage, cell cycle reentry, mitochondrial dysfunction, as well as its non-neuronal functions under physiological and pathological conditions. Moreover, we discuss evidence underscoring aberrant Cdk5 activity as a common theme observed in many neurodegenerative diseases.

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“…STZ is also used in in vitro experiments to explore the cellular mechanisms that might contribute to cell death in AD. It was found to have concentration-dependent cytotoxic effect in various neural cell types [ 29 – 32 ]. Mitochondrial damage [ 29 , 32 , 33 ], elevated reactive oxygen species production [ 34 ] and higher rate of apoptosis [ 33 – 35 ] were observed.…”

Section: Introductionmentioning

confidence: 99%

“…It was found to have concentration-dependent cytotoxic effect in various neural cell types [ 29 – 32 ]. Mitochondrial damage [ 29 , 32 , 33 ], elevated reactive oxygen species production [ 34 ] and higher rate of apoptosis [ 33 – 35 ] were observed. Its effect on insulin system was also examined showing reduced expression of insulin receptor substrate (IRS)-1 [ 36 ], altered GSK-3 phosphorylation [ 31 , 34 ] and increased tau protein phosphorylation [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

The Impact of Differentiation on Cytotoxicity and Insulin Sensitivity in Streptozotocin Treated SH-SY5Y Cells

Bagaméry

Kecsmár

et al. 2021

Neurochem Res

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Recently neuronal insulin resistance was suggested playing a role in Alzheimer’s disease. Streptozotocin (STZ) is commonly used to induce impairment in insulin metabolism. In our previous work on undifferentiated SH-SY5Y cells the compound exerted cytotoxicity without altering insulin sensitivity. Nevertheless, differentiation of the cells to a more mature neuron-like phenotype may considerably affect the significance of insulin signaling and its sensitivity to STZ. We aimed at studying the influence of STZ treatment on insulin signaling in SH-SY5Y cells differentiated by retinoic acid (RA). Cytotoxicity of STZ or low serum (LS) condition and protective effect of insulin were compared in RA differentiated SH-SY5Y cells. The effect of insulin and an incretin analogue, exendin-4 on insulin signaling was also examined by assessing glycogen synthase kinase-3 (GSK-3) phosphorylation. STZ was found less cytotoxic in the differentiated cells compared to our previous results in undifferentiated SH-SY5Y cells. The cytoprotective concentration of insulin was similar in the STZ and LS groups. However, the right-shifted concentration–response curve of insulin induced GSK-3 phosphorylation in STZ-treated differentiated cells is suggestive of the development of insulin resistance that was further confirmed by the insulin potentiating effect of exendin-4. Differentiation reduced the sensitivity of SH-SY5Y cells for the non-specific cytotoxicity of STZ and enhanced the relative significance of development of insulin resistance. The differentiated cells thus serve as a better model for studying the role of insulin signaling in neuronal survival. However, direct cytotoxicity of STZ also contributes to the cell death.

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

Cited by 28 publications

References 74 publications

Reduced Levels of Drp1 Protect against Development of Retinal Vascular Lesions in Diabetic Retinopathy

Reduced Levels of Drp1 Protect against Development of Retinal Vascular Lesions in Diabetic Retinopathy

Three decades of Cdk5

The Impact of Differentiation on Cytotoxicity and Insulin Sensitivity in Streptozotocin Treated SH-SY5Y Cells

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