Lymphocytic Mitochondrial Aconitase Activity is Reduced in Alzheimer's Disease and Mild Cognitive Impairment

Mangialasche, Francesca; Baglioni, Mauro; Cecchetti, Roberta; Kivipelto, Miia; Ruggiero, Carmelinda; Piobbico, Danilo; Kußmaul, Lothar; Monastero, Roberto; Brancorsini, Stefano; Mecocci, Patrizia

doi:10.3233/jad-142052

Cited by 39 publications

(32 citation statements)

References 52 publications

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“…Mitochondrial aconitase activity is reduced almost twofold in lymphocytes from AD relative to normal controls (Mangialasche et al ., 2015). ATP synthase α is found on the cell surface of neurons, where it binds oligomeric Aβ to initiate neurotoxicity (Xing et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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Section: Discussionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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“…Finally, 121 additional papers failed to meet the inclusion criteria. Therefore, this selection resulted in 17 studies that were identified to have as met the rigid inclusion criteria (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…In this review, all the selected studies should meet the following inclusion criteria: (1) the studies adopted a case-control study design based on a human population; (2) the studies evaluated the relationship between serum/plasma vitamin E and AD; (3) all patients were more than 60 years old; (4) the studies described the assessment standard of AD; (5) the studies provided sufficient information to calculate effect size; (6) all cases and controls had no vitamin E intake; (7) only English and Chinese articles were included. Any study that failed to meet the aforementioned criteria was excluded.…”

Section: Study Selectionmentioning

confidence: 99%

“…Mangialasche suggested that low‐plasma vitamin levels were associated with increased odds of AD. Other studies also led to conflicting conclusions. However, owing to differences in the criteria for AD, severity of AD among the different studies, contradictory results for the serum vitamin E levels between patients with AD and healthy controls were obtained.…”

Section: Introductionmentioning

confidence: 99%

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Do low‐serum vitamin E levels increase the risk of Alzheimer disease in older people? Evidence from a meta‐analysis of case‐control studies

Dong

Chen

Liu

et al. 2017

Int J Geriat Psychiatry

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“…Because of the iron‐sulfur group, ACO2 is sensitive to reactive oxygen species (ROS), which can affect ACO2 structure and activity . A decrease of ACO2 activity has been observed in some neurodegenerative diseases and senescence related to oxidative stress . These studies suggest that redox state has a significant effect on the activity of ACO2.…”

Section: Introductionmentioning

confidence: 99%

Zinc cooperates with p53 to inhibit the activity of mitochondrial aconitase through reactive oxygen species accumulation

Xue

Liu

et al. 2019

Cancer Medicine

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Metabolic reprogramming is a central hallmark of cancer. Therefore, targeting metabolism may provide an effective strategy for identifying promising drug targets for cancer treatment. In prostate cancer, cells undergo metabolic transformation from zinc‐accumulating, citrate‐producing cells to citrate‐oxidizing malignant cells with lower zinc levels and higher mitochondrial aconitase (ACO2) activity. ACO2 is a Krebs cycle enzyme that converts citrate to isocitrate and is sensitive to reactive oxygen species (ROS)‐mediated damage. In this study, we found that the expression of ACO2 is positively correlated with the malignancy of prostate cancer. Both zinc and p53 can lead to an increase in ROS. ACO2 can be a target for remodeling metabolism by sensing changes in the ROS levels of prostate cancer. Our results indicate that targeting ACO2 through zinc and p53 can change prostate cancer metabolism, and thus provides a potential new therapeutic strategy for prostate cancer.

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Lymphocytic Mitochondrial Aconitase Activity is Reduced in Alzheimer's Disease and Mild Cognitive Impairment

Abstract: Our results suggest that ACO2 activity is reduced in peripheral lymphocytes of subjects with AD and MCI and correlates with antioxidant protection. Further studies are warranted to verify the role of ACO2 in AD pathogenesis and its importance as a marker of AD progression.

Cited by 39 publications

References 52 publications

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Do low‐serum vitamin E levels increase the risk of Alzheimer disease in older people? Evidence from a meta‐analysis of case‐control studies

Zinc cooperates with p53 to inhibit the activity of mitochondrial aconitase through reactive oxygen species accumulation

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