A Signaling Lipid Associated with Alzheimer’s Disease Promotes Mitochondrial Dysfunction

Kennedy, Michael A.; Moffat, Tia C.; Gable, Kenneth; Ganesan, Suriakarthiga; Niewola-Staszkowska, Karolina; Johnston, Anne; Nislow, Corey; Giaever, Guri; Harris, Linda J.; Loewith, Robbie; Zaremberg, Vanina; Harper, Mary‐Ellen; Dunn, Teresa M.; Bennett, Steffany A. L.; Baetz, Kristin

doi:10.1038/srep19332

Cited by 28 publications

(19 citation statements)

References 51 publications

(68 reference statements)

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“…Spare respiratory capacity is viewed as an index of mitochondrial health and is a measure of how well a cell can produce energy under stressful energy-demanding conditions [13], [34]. Notably, there is evidence that decreased spare respiratory capacity is associated with cognitive impairment in rodent models of Alzheimer disease [33]. …”

Section: Discussionmentioning

confidence: 99%

Pifithrin-μ Prevents Cisplatin-Induced Chemobrain by Preserving Neuronal Mitochondrial Function

et al. 2017

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Cognitive impairment termed chemobrain is a common neurotoxicity associated with chemotherapy treatment, affecting an estimated 78% of patients. Prompted by the hypothesis that neuronal mitochondrial dysfunction underlies chemotherapy-induced cognitive impairment (CICI), we explored the efficacy of administering the small molecule pifithrin (PFT)-µ, an inhibitor of mitochondrial p53 accumulation, in preventing CICI. Male C57BL/6J mice injected with cisplatin +/− PFT-µ for two 5-day cycles were assessed for cognitive function using novel object/place recognition and alternation in a Y-maze. Cisplatin impaired performance in the novel object/place recognition and Y-maze tests. PFT-µ treatment prevented CICI and associated cisplatin-induced changes in coherency of myelin basic protein fibers in the cingular cortex and loss of doublecortin+ cells in the subventricular zone and hippocampal dentate gyrus. Mechanistically, cisplatin decreased spare respirator capacity of brain synaptosomes and caused abnormal mitochondrial morphology, which was counteracted by PFT-µ administration. Notably, increased mitochondrial p53 did not lead to cerebral caspase-3 activation or cytochrome-c release. Furthermore, PFT-µ administration did not impair the anticancer efficacy of cisplatin and radiotherapy in tumor-bearing mice. Our results supported the hypothesis that neuronal mitochondrial dysfunction induced by mitochondrial p53 accumulation is an underlying cause of CICI, and that PFT-µ may offer a tractable therapeutic strategy to limit this common side-effect of many types of chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Pifithrin-μ Prevents Cisplatin-Induced Chemobrain by Preserving Neuronal Mitochondrial Function

et al. 2017

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“…It is the most common mechanism of age-related degenerative processes. Mitochondria are the primary site for ROS production, and mitochondrial dysfunction leads to the overproduction of ROS followed by ATP depletion and ultimately cell death [50,131]. The major source of ROS is the superoxide anion radicals generated by the electron transport chain during oxidative phosphorylation.…”

Section: Attenuation Of Oxidative Stressmentioning

confidence: 99%

Neuroprotective Effects of Quercetin in Alzheimer’s Disease

et al. 2019

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Quercetin is a flavonoid with notable pharmacological effects and promising therapeutic potential. It is widely distributed among plants and found commonly in daily diets predominantly in fruits and vegetables. Neuroprotection by quercetin has been reported in several in vitro studies. It has been shown to protect neurons from oxidative damage while reducing lipid peroxidation. In addition to its antioxidant properties, it inhibits the fibril formation of amyloid-β proteins, counteracting cell lyses and inflammatory cascade pathways. In this review, we provide a synopsis of the recent literature exploring the relationship between quercetin and cognitive performance in Alzheimer’s disease and its potential as a lead compound in clinical applications.

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“…On the other hand, increased cellular ceramide levels have been reported for AD. A recent study in yeast and neuronal cell culture demonstrates that treatment with platelet-activating factor, which is neurotoxic and elevated in AD, promotes mitochondrial dysfunction and ROS accumulation, accompanied by an increase of ceramide levels (Kennedy et al 2016). Enhanced ceramide levels may lead to stabilization of β-secretase and promotion of amyloidogenic cleavage of APP to Aβ (Puglielli et al 2003).…”

Section: Pathological Alterations In Cholesterol and Ceramide Metabolismmentioning

confidence: 99%

Mitochondrial lipids in neurodegeneration

et al. 2016

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Mitochondrial dysfunction is a common feature of many neurodegenerative diseases, including proteinopathies such as Alzheimer’s or Parkinson’s disease, which are characterized by the deposition of aggregated proteins in the form of insoluble fibrils or plaques. The distinct molecular processes that eventually result in mitochondrial dysfunction during neurodegeneration are well studied but still not fully understood. However, defects in mitochondrial fission and fusion, mitophagy, oxidative phosphorylation and mitochondrial bioenergetics have been linked to cellular demise. These processes are influenced by the lipid environment within mitochondrial membranes as, besides membrane structure and curvature, recruitment and activity of different proteins also largely depend on the respective lipid composition. Hence, the interaction of neurotoxic proteins with certain lipids and the modification of lipid composition in different cell compartments, in particular mitochondria, decisively impact cell death associated with neurodegeneration. Here, we discuss the relevance of mitochondrial lipids in the pathological alterations that result in neuronal demise, focussing on proteinopathies.

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A Signaling Lipid Associated with Alzheimer’s Disease Promotes Mitochondrial Dysfunction

Cited by 28 publications

References 51 publications

Pifithrin-μ Prevents Cisplatin-Induced Chemobrain by Preserving Neuronal Mitochondrial Function

Pifithrin-μ Prevents Cisplatin-Induced Chemobrain by Preserving Neuronal Mitochondrial Function

Neuroprotective Effects of Quercetin in Alzheimer’s Disease

Mitochondrial lipids in neurodegeneration

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