Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity

Yuan, Yuan; Chen, Jingjiong; Ge, Xuhua; Deng, Jiangshan; Xu, Xiaofeng; Zhao, Yuwu; Wang, H.

doi:10.1002/2211-5463.13273

Cited by 15 publications

(13 citation statements)

References 54 publications

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“…Moreover, as believed, it is excessive mitochondrial ROS production as a result of mitochondrial dysfunction that leads to the development of many pathologies including AD [ 66 , 67 ]. Analysis of the different thus far described models have shown that AD is characterized by mitochondrial dysfunction, as inferred from the decreased mitochondrial membrane potential, respiration and ATP/ADP ratio, impaired mitochondrial trafficking in neurons [ 65 , 68 ], excessive mitochondrial fragmentation [ 69 , 70 , 71 ], and enhanced ROS production as a result of an imbalance between ROS formation and clearance [ 72 , 73 ].…”

Section: Discussionmentioning

confidence: 99%

Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42

Epremyan

Рогов

Goleva

et al. 2023

IJMS

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Alzheimer’s disease (AD) is an incurable, age-related neurological disorder, the most common form of dementia. Considering that AD is a multifactorial complex disease, simplified experimental models are required for its analysis. For this purpose, genetically modified Yarrowia lipolytica yeast strains expressing Aβ42 (the main biomarker of AD), eGFP-Aβ42, Aβ40, and eGFP-Aβ40 were constructed and examined. In contrast to the cells expressing eGFP and eGFP-Aβ40, retaining “normal” mitochondrial reticulum, eGFP-Aβ42 cells possessed a disturbed mitochondrial reticulum with fragmented mitochondria; this was partially restored by preincubation with a mitochondria-targeted antioxidant SkQThy. Aβ42 expression also elevated ROS production and cell death; low concentrations of SkQThy mitigated these effects. Aβ42 expression caused mitochondrial dysfunction as inferred from a loose coupling of respiration and phosphorylation, the decreased level of ATP production, and the enhanced rate of hydrogen peroxide formation. Therefore, we have obtained the same results described for other AD models. Based on an analysis of these and earlier data, we suggest that the mitochondrial fragmentation might be a biomarker of the earliest preclinical stage of AD with an effective therapy based on mitochondria- targeted antioxidants. The simple yeast model constructed can be a useful platform for the rapid screening of such compounds.

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Section: Discussionmentioning

confidence: 99%

Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42

Epremyan

Рогов

Goleva

et al. 2023

IJMS

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“…Activated signal-regulated kinase phosphorylates Drp1, Dynamin-related protein 1, and promotes mitochondrial fission. Mdivi-1 inhibits ischemia and hypoxia-induced Aβ generation and mitochondrial fission [ 155 ].…”

Section: Conditions That Impact Amyloid Beta Toxicitymentioning

confidence: 99%

Amyloid Beta in Aging and Alzheimer’s Disease

Sehar

Rawat

Reddy

et al. 2022

IJMS

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Alzheimer’s disease (AD), is a progressive neurodegenerative disease that affects behavior, thinking, learning, and memory in elderly individuals. AD occurs in two forms, early onset familial and late-onset sporadic; genetic mutations in PS1, PS2, and APP genes cause early onset familial AD, and a combination of lifestyle, environment and genetic factors causes the late-onset sporadic form of the disease. However, accelerated disease progression is noticed in patients with familial AD. Disease-causing pathological changes are synaptic damage, and mitochondrial structural and functional changes, in addition to increased production and accumulation of phosphorylated tau (p-tau), and amyloid beta (Aβ) in the affected brain regions in AD patients. Aβ is a peptide derived from amyloid precursor protein (APP) by proteolytic cleavage of beta and gamma secretases. APP is a glycoprotein that plays a significant role in maintaining neuronal homeostasis like signaling, neuronal development, and intracellular transport. Aβ is reported to have both protective and toxic effects in neurons. The purpose of our article is to summarize recent developments of Aβ and its association with synapses, mitochondria, microglia, astrocytes, and its interaction with p-tau. Our article also covers the therapeutic strategies that reduce Aβ toxicities in disease progression and discusses the reasons for the failures of Aβ therapeutics.

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“…A recent study suggests that Drp1‐mediated hypoxia‐associated increases in the BACE1 activation and Aβ accumulation in a cellular model of AD (Yuan et al, 2021). The study holds significance as it was the first upstream effect of Drp1 on Aβ that was recognized.…”

Section: Role Of Drp1 In Admentioning

confidence: 99%

Mechanistic and therapeutic role of Drp1 in the pathogenesis of Alzheimer's disease

Bera

Lavanya

Reshmi

et al. 2022

Eur J of Neuroscience

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Alzheimer's disease (AD), a progressive neurodegenerative disorder, has emerged as the most common form of dementia in the elderly. Two major pathological hallmarks have been identified for AD: extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT). Recently, dynaminrelated protein 1 (Drp1) was recognized to contribute significantly towards the pathogenesis of AD. Drp1 is primarily located in the cytosol, from where it translocates to the mitochondrial outer membrane and drives the mitochondrial fission via GTP hydrolysis. Drp1 interacts with Aβ and phosphorylated tau, leading to excessive mitochondrial fragmentation, which in turn results in synaptic dysfunction, neuronal damage and cognitive decline. Several studies suggest an increase in the level of Drp1 in the post-mortem brain specimen collected from the AD patients and murine models of AD. Interestingly, heterozygous deletion of Drp1 in the transgenic murine model of AD ameliorates the mitochondrial dysfunction, improving learning and memory. The current review article discusses the possible mechanistic pathways by which Drp1 can influence the pathogenesis of AD. Besides, it will describe various inhibitors for Drp1 and their potential role as therapeutics for AD in the future.

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Activation of ERK–Drp1 signaling promotes hypoxia‐induced Aβ accumulation by upregulating mitochondrial fission and BACE1 activity

Cited by 15 publications

References 54 publications

Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42

Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42

Amyloid Beta in Aging and Alzheimer’s Disease

Mechanistic and therapeutic role of Drp1 in the pathogenesis of Alzheimer's disease

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