ABAD Directly Links Aß to Mitochondrial Toxicity in Alzheimer's Disease

Lustbader, Joyce W.; Cirilli, Maurizio; Lin, Chang; Xu, Hongwei; Takuma, Kazuhiro; Wang, Ning; Caspersen, Casper; Chen, Xi; Pollak, Susan; Chaney, Michael O.; Trinchese, Fabrizio; Liu, Shumin; Gunn-Moore, Frank J.; Lue, Lih‐Fen; Walker, Douglas G.; Kuppusamy, Periannan; Zewier, Zay L.; Arancio, Ottavio; Stern, David M.; Yan, Shirley ShiDu; Wu, Hao

doi:10.1126/science.1091230

Cited by 1,188 publications

(1,210 citation statements)

References 21 publications

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“…Supporting Information Available: Synthetic procedures for compounds 1-10, enzymology assay, cell imaging protocols, and complete ref 8. This material is available free of charge via the Internet at http://pubs.acs.org.…”

Section: Discussionmentioning

confidence: 99%

Harnessing Functional Plasticity of Enzymes: A Fluorogenic Probe for Imaging 17β-HSD10 Dehydrogenase, an Enzyme Involved in Alzheimer's and Parkinson's Diseases

Froemming

Sameš

2007

J. Am. Chem. Soc.

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Abstract:In this paper, we describe the development of a fluorogenic substrate for 17 -hydroxysteroiddehydrogenase type 10 (17 -HSD10), which is a multifunctional metabolic enzyme fulfilling several metabolic roles ( -oxidation of fatty acids, catabolism of isoleucine, and metabolism of steroids). In recent years, it has emerged as an important stress and pathological marker in neurons and glial cells (expression downregulation in Parkinson's disease, up-regulation and association with -amyloid peptide in Alzheimer's disease). Through the iterative molecular design and chemical synthesis described herein, compound 1 was developed, which possesses all required properties for a selective optical reporter substrate: alcoholketone optical switching, the ability to function as a good enzyme substrate (expressed in kinetic parameters), cell permeability, and cell retention. Probe 1 provides a blue-to-green/yellow bright switch and enables non-invasive, real-time imaging of 17 -HSD10 in live human cells. The selectivity of reporter 1 was established by the quantitative correlation of metabolic activity to protein expression in human kidney cell line HEK-293T.

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Section: Discussionmentioning

confidence: 99%

Harnessing Functional Plasticity of Enzymes: A Fluorogenic Probe for Imaging 17β-HSD10 Dehydrogenase, an Enzyme Involved in Alzheimer's and Parkinson's Diseases

Froemming

Sameš

2007

J. Am. Chem. Soc.

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“…The Aβ peptide can also potentially cause mPTP opening in vivo as it induces mitochondrial swelling, decreases mitochondrial membrane potential, and potentiates the effect of mPTP inducers in isolated brain mitochondria (Du et al., 2008; Moreira, Santos, Moreno, & Oliveira, 2001; Shevtzova, Kireeva, & Bachurin, 2001). This can be due to an indirect effect on the pore as the Aβ peptide has the ability to enhance intracellular calcium (Abramov, Canevari, & Duchen, 2004; Chin, Tse, Harris, & Jhamandas, 2006) and to induce oxidative stress (Lustbader et al., 2004; Reddy & Beal, 2008), which is increasingly recognized as a key factor in neurodegenerative disorders. These effects are possible mechanisms contributing to mPTP opening.…”

Section: Evidence For the Involvement Of Mptp Opening In Age‐associatmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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SummaryThe cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.

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“…Lustbader et al, demonstrated that Aβ binds to the mitochondrial β-amyloid-binding alcohol dehydrogenase (ABAD) (Lustbader et al, 2004), an up-regulated enzyme in patients' brain, which resulted in free radical production and oxidative stress, and increased expression of the cytosolic antioxidant enzyme peroxiredoxin II as a cellular defense response (Yao et al, 2007;Ahsan et al, 2009). In fact, the inhibition of the Aβ-ABAD interaction has been shown to reduce Aβ accumulation and to improve mitochondrial function in transgenic mice and neuroblastoma cells (Lim et al, 2011;Yao et al, 2011).…”

Section: In Alzheimer´s Diseasementioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

140

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For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

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ABAD Directly Links Aß to Mitochondrial Toxicity in Alzheimer's Disease

Cited by 1,188 publications

References 21 publications

Harnessing Functional Plasticity of Enzymes: A Fluorogenic Probe for Imaging 17β-HSD10 Dehydrogenase, an Enzyme Involved in Alzheimer's and Parkinson's Diseases

Harnessing Functional Plasticity of Enzymes: A Fluorogenic Probe for Imaging 17β-HSD10 Dehydrogenase, an Enzyme Involved in Alzheimer's and Parkinson's Diseases

Mitochondria and aging: A role for the mitochondrial transition pore?

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

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