Publications by authors named "D Allan Butterfield"

620 Publications

mTOR in Alzheimer disease and its earlier stages: Links to oxidative damage in the progression of this dementing disorder.

Free Radic Biol Med 2021 Apr 30;169:382-396. Epub 2021 Apr 30.

Department of Chemistry, Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy; Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40506-0055, USA. Electronic address:

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population and has worldwide impact. The etiology of the disease is complex and results from the confluence of multiple mechanisms ultimately leading to neuronal loss and cognitive decline. Among risk factors, aging is the most relevant and accounts for several pathogenic events that contribute to disease-specific toxic mechanisms. Accumulating evidence linked the alterations of the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase playing a key role in the regulation of protein synthesis and degradation, to age-dependent cognitive decline and pathogenesis of AD. To date, growing studies demonstrated that aberrant mTOR signaling in the brain affects several pathways involved in energy metabolism, cell growth, mitochondrial function and proteostasis. Recent advances associated alterations of the mTOR pathway with the increased oxidative stress. Disruption of all these events strongly contribute to age-related cognitive decline including AD. The current review discusses the main regulatory roles of mTOR signaling network in the brain, focusing on its role in autophagy, oxidative stress and energy metabolism. Collectively, experimental data suggest that targeting mTOR in the CNS can be a valuable strategy to prevent/slow the progression of AD.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.04.025DOI Listing
April 2021

Seafloor Incubation Experiment with Deep-Sea Hydrothermal Vent Fluid Reveals Effect of Pressure and Lag Time on Autotrophic Microbial Communities.

Appl Environ Microbiol 2021 04 13;87(9). Epub 2021 Apr 13.

Marine Chemistry and Geochemistry, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts, USA

Depressurization and sample processing delays may impact the outcome of shipboard microbial incubations of samples collected from the deep sea. To address this knowledge gap, we developed a remotely operated vehicle (ROV)-powered incubator instrument to carry out and compare results from and shipboard RNA stable isotope probing (RNA-SIP) experiments to identify the key chemolithoautotrophic microbes and metabolisms in diffuse, low-temperature venting fluids from Axial Seamount. All the incubations showed microbial uptake of labeled bicarbonate primarily by thermophilic autotrophic that oxidized hydrogen coupled with nitrate reduction. However, the seafloor incubations showed higher abundances of transcripts annotated for aerobic processes, suggesting that oxygen was lost from the hydrothermal fluid samples prior to shipboard analysis. Furthermore, transcripts for thermal stress proteins such as heat shock chaperones and proteases were significantly more abundant in the shipboard incubations, suggesting that depressurization induced thermal stress in the metabolically active microbes in these incubations. Together, the results indicate that while the autotrophic microbial communities in the shipboard and seafloor experiments behaved similarly, there were distinct differences that provide new insight into the activities of natural microbial assemblages under nearly native conditions in the ocean. Diverse microbial communities drive biogeochemical cycles in Earth's ocean, yet studying these organisms and processes is often limited by technological capabilities, especially in the deep ocean. In this study, we used a novel marine microbial incubator instrument capable of experimentation to investigate microbial primary producers at deep-sea hydrothermal vents. We carried out identical stable isotope probing experiments coupled to RNA sequencing both on the seafloor and on the ship to examine thermophilic, microbial autotrophs in venting fluids from an active submarine volcano. Our results indicate that microbial communities were significantly impacted by the effects of depressurization and sample processing delays, with shipboard microbial communities being more stressed than seafloor incubations. Differences in metabolism were also apparent and are likely linked to the chemistry of the fluid at the beginning of the experiment. Microbial experimentation in the natural habitat provides new insights into understanding microbial activities in the ocean.
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http://dx.doi.org/10.1128/AEM.00078-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091007PMC
April 2021

Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: A harmful synergistic path in down syndrome.

Free Radic Biol Med 2021 Mar 29;165:152-170. Epub 2021 Jan 29.

Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy. Electronic address:

Dysregulation of brain insulin signaling with reduced downstream neuronal survival and plasticity mechanisms are fundamental abnormalities observed in Alzheimer disease (AD). This phenomenon, known as brain insulin resistance, is associated with poor cognitive performance and is driven by the inhibition of IRS1. Since Down syndrome (DS) and AD neuropathology share many common features, we investigated metabolic aspects of neurodegeneration in DS and whether they contribute to early onset AD in DS. We evaluated levels and activation of proteins belonging to the insulin signaling pathway (IR, IRS1, BVR-A, MAPK, PTEN, Akt, GSK3β, PKCζ, AS160, GLUT4) in the frontal cortex of Ts65dn (DS model) (n = 5-6/group) and euploid mice (n = 6/group) at different ages (1, 3, 9 and 18 months). Furthermore, we analyzed whether changes of brain insulin signaling were associated with alterations of: (i) proteins regulating brain energy metabolism (mitochondrial complexes, hexokinase-II, Sirt1); (ii) oxidative stress (OS) markers (iii) APP cleavage; and (iv) proteins mediating synaptic plasticity mechanisms (PSD95, syntaxin-1 and BDNF). Ts65dn mice showed an overall impairment of the above-mentioned pathways, mainly characterized by defects of proteins activation state. Such alterations start early in life (at 1 month, during brain maturation). In particular, accumulation of inhibited IRS1, together with the uncoupling among the proteins downstream from IRS1 (brain insulin resistance), characterize Ts65dn mice. Furthermore, reduced levels of mitochondrial complexes and Sirt1, as well as increased indices of OS also were observed. These alterations precede the accumulation of APP-C99 in Ts65dn mice. Tellingly, oxidative stress levels were negatively associated with IR, IRS1 and AS160 activation as well as mitochondrial complexes levels in Ts65dn mice, suggesting a role for oxidative stress in the observed alterations. We propose that a close link exists among brain insulin resistance, mitochondrial defects and OS that contributes to brain dysfunctions observed in DS, likely favoring the development of AD in DS.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.01.042DOI Listing
March 2021

Fidelity of the PINK1 knockout rat to oxidative stress and other characteristics of Parkinson disease.

Free Radic Biol Med 2021 Feb 13;163:88-101. Epub 2020 Dec 13.

Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40506, USA. Electronic address:

Parkinson disease (PD) is the second most common age-related neurodegenerative disease in the world, and PD significantly impacts the quality of life, especially as in general people are living longer. Because of the numerous and complex features of sporadic PD that progressively develops, it is difficult to build an ideal animal model for PD research. Genetically modified PD rodent animal models are considered as a major tool with which to study the mechanisms and potential therapeutic targets for PD. Up to now, none of the rodent animal models displays all PD characteristics. The Michael J. Fox Foundation for Parkinson's Research (MJFF) funded SAGE Laboratories to generate a PTEN-induced putative kinase-1 (PINK1) knockout (KO) rat model for familial PD using zinc finger nuclease (ZFN) technology. In the current paper, we review all papers from PubMed that report studies with PINK1 KO rats, presenting the research results, and discussing the fidelity of this rat model to PD according to its phenotypes studied by several laboratories. This review will serve as a critical reference for future studies with this rodent model, providing a better understanding of PD etiology, pathology, and potential treatment strategies.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.12.004DOI Listing
February 2021

Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease.

Antioxidants (Basel) 2020 Sep 2;9(9). Epub 2020 Sep 2.

Department of Chemistry and Biochemistry University of Mount Union Alliance, OH 44601, USA.

Oxidative and nitrosative stress are widely recognized as critical factors in the pathogenesis and progression of Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI). A major source of free radicals that lead to oxidative and nitrosative damage is mitochondria. This review paper discusses oxidative and nitrosative stress and markers thereof in the brain, along with redox proteomics, which are techniques that have been pioneered in the Butterfield laboratory. Selected biological alterations in-and oxidative and nitrosative modifications of-mitochondria in AD and MCI and systems of relevance thereof also are presented. The review article concludes with a section on the implications of mitochondrial oxidative and nitrosative stress in MCI and AD with respect to imaging studies in and targeted therapies toward these disorders. Taken together, this review provides support for the notion that brain mitochondrial alterations in AD and MCI are key components of oxidative and nitrosative stress observed in these two disorders, and as such, they provide potentially promising therapeutic targets to slow-and hopefully one day stop-the progression of AD, which is a devastating dementing disorder.
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http://dx.doi.org/10.3390/antiox9090818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554713PMC
September 2020