Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice

Stojakovic, Andrea; Trushin, Sergey; Sheu, Anthony; Khalili, Layla; Su, Chang; Li, Xing; Christensen, Trace; Salisbury, Jeffrey L.; Geroux, Rachel E.; Gateno, Benjamin; Flannery, Padraig J.; Dehankar, Mrunal; Funk, Cory C.; Wilkins, Jordan; Степанова, Анна; O’Hagan, Tara; Galkin, Alexander; Nesbitt, Jarred J.; Zhu, Xinyuan; Tripathi, Utkarsh; Macura, Slobodan; Tchkonia, Tamar; Pirtskhalava, Tamar; Kirkland, James L.; Kudgus, Rachel A.; Schoon, Renée A.; Reid, Joel M.; Yu, Yun William; Kanekiyo, Takahisa; Zhang, Song; Nemutlu, Emirhan; Dzeja, Petras P.; Jaspersen, Adam; Kwon, Ye In Christopher; Lee, Michael K.; Trushina, Eugenia

doi:10.1038/s42003-020-01584-y

Cited by 46 publications

(118 citation statements)

References 86 publications

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“…We followed a protocol described previously [ 20 , 21 ]. Briefly, for histopathological analyses, mice were sacrificed and perfused intracardially with 4% paraformaldehyde and cryoprotected in 30% sucrose solution.…”

Section: Methodsmentioning

confidence: 99%

γ-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer’s Disease-like Pathology and Neurodegeneration in a Mouse Model

et al. 2021

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Oxidative stress in Alzheimer’s disease (AD) is mediated, in part, by the loss of glutathione (GSH). Previous studies show that γ-glutamyl transpeptidase (GGT)-resistant GSH analog, Ψ-GSH, improves brain GSH levels, reduces oxidative stress markers in brains of APP/PS1 transgenic mice, a mouse model of AD, and attenuates early memory deficits in the APP/PS1 model. Herein, we examined whether Ψ-GSH can attenuate the disease progression when administered following the onset of AD-like pathology in vivo. Cohorts of APP/PS1 mice were administered Ψ-GSH for 2 months starting at 8 month or 12 months of age. We show that Ψ-GSH treatment reduces indices of oxidative stress in older mice by restoration of enzyme glyoxalase-1 (Glo-1) activity and reduces levels of insoluble Aβ. Quantitative neuropathological analyses show that Ψ-GSH treatment significantly reduces Aβ deposition and brain inflammation in APP/PS1 mice compared to vehicle-treated mice. More importantly, Ψ-GSH treatment attenuated the progressive loss of cortical TH+ afferents and the loss of TH+ neurons in the locus coeruleus (LC). Collectively, the results show that Ψ-GSH exhibits significant antioxidant activity in aged APP/PS1 mice and chronic Ψ-GSH treatment administered after the onset of AD pathology can reverse/slow further progression of AD-like pathology and neurodegeneration in vivo.

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Section: Methodsmentioning

confidence: 99%

γ-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer’s Disease-like Pathology and Neurodegeneration in a Mouse Model

et al. 2021

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“…It is possible that mitochondrial ROS-driven glycolytic switch reprograms neuron metabolism in such a way that the production of energy through glycolysis does not match the high energetic demands of the neuron, thus, facilitating its entry into apoptosis. Interestingly, modulation of CI has been associated with development of both PD and Alzheimer's disease (AD; [116][117][118]). Given that CI can undergo activation and deactivation, and both are related to different modes of ROS production, it would be important to ascertain whether the different physiological states of CI are related to the pathogenesis in neurological disorders.…”

Section: Mitochondrial Ros Production In (Patho)physiologymentioning

confidence: 99%

Generation of Reactive Oxygen Species by Mitochondria

2021

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Reactive oxygen species (ROS) are series of chemical products originated from one or several electron reductions of oxygen. ROS are involved in physiology and disease and can also be both cause and consequence of many biological scenarios. Mitochondria are the main source of ROS in the cell and, particularly, the enzymes in the electron transport chain are the major contributors to this phenomenon. Here, we comprehensively review the modes by which ROS are produced by mitochondria at a molecular level of detail, discuss recent advances in the field involving signalling and disease, and the involvement of supercomplexes in these mechanisms. Given the importance of mitochondrial ROS, we also provide a schematic guide aimed to help in deciphering the mechanisms involved in their production in a variety of physiological and pathological settings.

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“…AD pathogenesis has been linked to mitochondria as their health is essential in maintaining energy homeostasis and in preventing neuronal dysfunction. Stojakovic et al observed that mitochondrial respiratory chain complex I might be a therapeutic target in AD [ 129 ]. Chronic treatment with complex I inhibitor, the tricyclic pyrone (CP2), which can penetrate the blood brain barrier (BBB) and accumulate in mitochondria, improves cognitive and motor function in transgenic mice, expressing a form of the amyloid precursor protein (APP) and presenilin 1 that leads to early onset AD (APP/PS1).…”

Section: Focus On Experimental Models Of Ad and Potential Antioxidant Therapeutic Targetsmentioning

confidence: 99%

“…Further, this treatment can reduce total Aβ levels triggering autophagy, one of the neuroprotective pathways essential for Aβ clearance. Taken together, the data suggest that CP2 treatment induces multiple protective mechanisms including autophagy, anti-inflammatory, and antioxidant responses, which contribute to reduce Aβ pathology [ 129 ].…”

Section: Focus On Experimental Models Of Ad and Potential Antioxidant Therapeutic Targetsmentioning

confidence: 99%

Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

et al. 2021

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Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

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Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice

Cited by 46 publications

References 86 publications

γ-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer’s Disease-like Pathology and Neurodegeneration in a Mouse Model

γ-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer’s Disease-like Pathology and Neurodegeneration in a Mouse Model

Generation of Reactive Oxygen Species by Mitochondria

Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

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