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Alzheimer Disease: HELP
Articles by David Allan Butterfield
Based on 101 articles published since 2010
(Why 101 articles?)
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Between 2010 and 2020, D. A. Butterfield wrote the following 101 articles about Alzheimer Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
1 Editorial Down syndrome: From development to adult life to Alzheimer disease. 2018

Butterfield, D Allan / Perluigi, Marzia. ·Department of Chemistry and Sanders-Brown, Center on Aging, University of Kentucky, Lexington, KY 40506 USA. · Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy. ·Free Radic Biol Med · Pubmed #29079527.

ABSTRACT: -- No abstract --

2 Editorial mTOR: Alzheimer's disease prevention for APOE4 carriers. 2016

Lin, Ai-Ling / Butterfield, D Allan / Richardson, Arlan. ·Sanders-Brown Center on Aging, Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA. · Sanders-Brown Center on Aging, Department of Biomedical Engineering, University of Kentucky, Lexington, Kentucky, USA. ·Oncotarget · Pubmed #27385004.

ABSTRACT: -- No abstract --

3 Editorial Redox proteomics. 2012

Butterfield, D Allan / Dalle-Donne, Isabella. · ·Antioxid Redox Signal · Pubmed #22671972.

ABSTRACT: Proteins are major targets of reactive oxygen and nitrogen species (ROS/RNS) and numerous post-translational, reversible or irreversible modifications have been characterized, which may lead to a change in the structure and/or function of the oxidized protein. Redox proteomics is an increasingly emerging branch of proteomics aimed at identifying and quantifying redox-based changes within the proteome both in redox signaling and under oxidative stress conditions. Correlation between protein oxidation and human disease is widely accepted, although elucidating cause and effect remains a challenge. Increasing biomedical data have provided compelling evidences for the involvement of perturbations in redox homeostasis in a large number of pathophysiological conditions and aging. Research toward a better understanding of the molecular mechanisms of a disease together with identification of specific targets of oxidative damage is urgently required. This is the power and potential of redox proteomics. In the last few years, combined proteomics, mass spectrometry (MS), and affinity chemistry-based methodologies have contributed in a significant way to provide a better understanding of protein oxidative modifications occurring in various biological specimens under different physiological and pathological conditions. Hence, this Forum on Redox Proteomics is timely. Original and review articles are presented on various subjects ranging from redox proteomics studies of oxidatively modified brain proteins in Alzheimer disease and animal models of Alzheimer and Parkinson disease, to potential new biomarker discovery paradigm for human disease, to chronic kidney disease, to protein nitration in aging and age-related neurodegenerative disorders, electrophile-responsive proteomes of special relevance to diseases involving mitochondrial alterations, to cardiovascular physiology and pathology.

4 Review BRAIN LIPID PEROXIDATION AND ALZHEIMER DISEASE: SYNERGY BETWEEN THE BUTTERFIELD AND MATTSON LABORATORIES. 2020

Butterfield, D Allan. ·Department of Chemistry and Sanders-Brown Center on Aging, University Of Kentucky, Lexington, KY, 40506, United States. Electronic address: dabcns@uky.edu. ·Ageing Res Rev · Pubmed #32205035.

ABSTRACT: Brains from persons with Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI), exhibit high levels of oxidative damage, including that to phospholipids. One type of oxidative damage is lipid peroxidation, the most important index of which is protein-bound 4-hydroxy-2-trans-nonenal (HNE). This highly reactive alkenal changes the conformations and lowers the activities of brain proteins to which HNE is covalently bound. Evidence exists that suggests that lipid peroxidation is the first type of oxidative damage associated with amyloid β-peptide (Aβ), a 38-42 amino acid peptide that is highly neurotoxic and critical to the pathophysiology of AD. The Butterfield laboratory is one of, if not the, first research group to show that Aβ42 oligomers led to lipid peroxidation and to demonstrate this modification in brains of subjects with AD and MCI. The Mattson laboratory, particularly when Dr. Mattson was a faculty member at the University of Kentucky, also showed evidence for lipid peroxidation associated with Aβ peptides, mostly in in vitro systems. Consequently, there is synergy between our two laboratories. Since this special tribute issue of Aging Research Reviews is dedicated to the career of Dr. Mattson, a review of some aspects of this synergy of lipid peroxidation and its relevance to AD, as well as the role of lipid peroxidation in the progression of this dementing disorder seems germane. Accordingly, this review outlines some of the individual and/or complementary research on lipid peroxidation related to AD published from our two laboratories either separately or jointly.

5 Review Apolipoprotein E and oxidative stress in brain with relevance to Alzheimer's disease. 2020

Butterfield, D Allan / Mattson, Mark P. ·Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA. Electronic address: dabcns@uky.edu. · Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA. ·Neurobiol Dis · Pubmed #32036033.

ABSTRACT: Inheritance of apolipoprotein E4 (APOE4) is a major risk factor for development of Alzheimer's disease (AD). This lipoprotein, in contrast to apoE2, has arginine residues at positions 112 and 158 in place of cysteines in the latter isoform. In apoE3, the Cys at residue 158 is replaced by an arginine residue. This differential amino acid composition of the three genotypes of APOE have profound influence on the structure, binding properties, and multiple functions of this lipoprotein. Moreover, AD brain is under a high degree of oxidative stress, including that associated with amyloid β-peptide (Aβ) oligomers. Lipid peroxidation produces the highly reactive and neurotoxic molecule, 4-hydroxynonenal (HNE) that forms covalent bonds with cysteine residues (Cys) [as well as with Lys and His residues]. Covalently modified Cys significantly alter structure and function of modified proteins. HNE bound to Cys residue(s) on apoE2 and apoE3 lessens the chance of HNE damage other proteins. apoE4, lacking Cys residues, is unable to scavenge HNE, permitting this latter neurotoxic molecule to lead to oxidative modification of neuronal proteins and eventual cell death. We posit that this lack of HNE scavenging activity in apoE4 significantly contributes to the association of APOE4 inheritance and increased risk of developing AD. Apoe knock-out mice provide insights into the role of this lipoprotein in oxidative stress. Targeted replacement mice in which the mouse gene of Apoe is separately replaced by the human APOE2, APOE3, or APOE4 genes, while keeping the mouse promoter assures the correct location and amount of the human protein isoform. Human APOE targeted replacement mice have been used to investigate the notion that oxidative damage to and death of neurons in AD and its earlier stages is related to APOE genotype. This current paper reviews the intersection of human APOE genotype, oxidative stress, and diminished function of this lipoprotein as a major contributing risk factor for development of AD. Discussion of potential therapeutic strategies to mitigate against the elevated risk of developing AD with inheritance of the APOE4 allele also is presented.

6 Review Phosphoproteomics of Alzheimer disease brain: Insights into altered brain protein regulation of critical neuronal functions and their contributions to subsequent cognitive loss. 2019

Butterfield, D Allan. ·Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA. Electronic address: dabcns@uky.edu. ·Biochim Biophys Acta Mol Basis Dis · Pubmed #31167728.

ABSTRACT: Alzheimer disease (AD) is the major locus of dementia worldwide. In the USA there are nearly 6 million persons with this disorder, and estimates of 13-20 million AD cases in the next three decades. The molecular bases for AD remain unknown, though processes involving amyloid beta-peptide as small oligomeric forms are gaining attention as known agents to both lead to oxidative stress and synaptic dysfunction associated with cognitive dysfunction in AD and its earlier forms, including amnestic mild cognitive impairment (MCI) and possibly preclinical Alzheimer disease (PCAD). Altered brain protein phosphorylation is a hallmark of AD, and phosphoproteomics offers an opportunity to identify these altered phosphoproteins in order to gain more insights into molecular mechanisms of neuronal dysfunction and death that lead to cognitive loss. This paper reviews what, to this author, are believed to be the known phosphoproteomics studies related to in vitro and in vivo models of AD as well as phosphoproteomics studies of brains from subjects with AD, and in at least one case in MCI and PCAD as well. The results of this review are discussed with relevance to new insights into AD brain protein dysregulation in critical neuronal functions and to potential therapeutic targets to slow, or in favorable cases, halt progression of this dementing disorder that affects millions of persons and their families worldwide.

7 Review Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. 2019

Butterfield, D Allan / Halliwell, Barry. ·Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. · Department of Biochemistry and Centre for Ageing and Neurobiology, National University of Singapore, Singapore, Singapore. bchbh@nus.edu.sg. ·Nat Rev Neurosci · Pubmed #30737462.

ABSTRACT: Alzheimer disease (AD) is a major cause of age-related dementia. We do not fully understand AD aetiology and pathogenesis, but oxidative damage is a key component. The brain mostly uses glucose for energy, but in AD and amnestic mild cognitive impairment glucose metabolism is dramatically decreased, probably owing, at least in part, to oxidative damage to enzymes involved in glycolysis, the tricarboxylic acid cycle and ATP biosynthesis. Consequently, ATP-requiring processes for cognitive function are impaired, and synaptic dysfunction and neuronal death result, with ensuing thinning of key brain areas. We summarize current research on the interplay and sequence of these processes and suggest potential pharmacological interventions to retard AD progression.

8 Review Redox proteomics and amyloid β-peptide: insights into Alzheimer disease. 2019

Butterfield, D Allan / Boyd-Kimball, Debra. ·Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA. · Department of Chemistry and Biochemistry, University of Mount Union, Alliance, Ohio, USA. ·J Neurochem · Pubmed #30216447.

ABSTRACT: Alzheimer disease (AD) is a progressive neurodegenerative disorder associated with aging and characterized pathologically by the presence of senile plaques, neurofibrillary tangles, and neurite and synapse loss. Amyloid beta-peptide (1-42) [Aβ(1-42)], a major component of senile plaques, is neurotoxic and induces oxidative stress in vitro and in vivo. Redox proteomics has been used to identify proteins oxidatively modified by Aβ(1-42) in vitro and in vivo. In this review, we discuss these proteins in the context of those identified to be oxidatively modified in animal models of AD, and human studies including familial AD, pre-clinical AD (PCAD), mild cognitive impairment (MCI), early AD, late AD, Down syndrome (DS), and DS with AD (DS/AD). These redox proteomics studies indicate that Aβ(1-42)-mediated oxidative stress occurs early in AD pathogenesis and results in altered antioxidant and cellular detoxification defenses, decreased energy yielding metabolism and mitochondrial dysfunction, excitotoxicity, loss of synaptic plasticity and cell structure, neuroinflammation, impaired protein folding and degradation, and altered signal transduction. Improved access to biomarker imaging and the identification of lifestyle interventions or treatments to reduce Aβ production could be beneficial in preventing or delaying the progression of AD. This article is part of the special issue "Proteomics".

9 Review Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer's Disease. 2018

Butterfield, D Allan / Boyd-Kimball, Debra. ·Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. · Department of Chemistry and Biochemistry, University of Mount Union, Alliance, OH, USA. ·J Alzheimers Dis · Pubmed #29562527.

ABSTRACT: Oxidative stress is implicated in the pathogenesis and progression of Alzheimer's disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-β peptide, Aβ1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aβ1-42, but not in Aβ1-42-poor regions, and was among the first to demonstrate Aβ peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. Identification of oxidatively modified brain proteins by the methods of redox proteomics was pioneered in the Butterfield laboratory. Four recurring altered pathways secondary to oxidative damage in brain from persons with AD, aMCI, or Down syndrome with AD are interrelated and contribute to neuronal death. This "Quadrilateral of Neuronal Death" includes altered: glucose metabolism, mTOR activation, proteostasis network, and protein phosphorylation. Some of these pathways are altered even in brains of persons with preclinical AD. We opine that targeting these pathways pharmacologically and with lifestyle changes potentially may provide strategies to slow or perhaps one day, prevent, progression or development of this devastating dementing disorder. This invited review outlines both in vitro and in vivo studies from the Butterfield laboratory related to Aβ1-42 and AD and discusses the importance and implications of some of the major achievements of the Butterfield laboratory in AD research.

10 Review Perspectives on Oxidative Stress in Alzheimer's Disease and Predictions of Future Research Emphases. 2018

Butterfield, D Allan. ·Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. ·J Alzheimers Dis · Pubmed #29504538.

ABSTRACT: Oxidative stress, an overproduction of free radicals or a diminution of free radical scavenging ability relative to those of cognitively aged-matched controls, is widely recognized as a critical component of the pathogenesis and progression of Alzheimer's disease (AD). This recognition arose in significant part from the work in the author's laboratory, complemented by research from others' laboratories. The Butterfield laboratory discovered the oxidative stress associated with oligomeric amyloid-β peptide manifested primarily as elevated oxidative modification of proteins and peroxidation of lipids. Such oxidative damage caused neuronal death, which undoubtedly underlies the progressive loss of cognition in AD. Identification of specific oxidatively modified brain proteins in subjects with AD or amnestic mild cognitive impairment was achieved by the methods of redox proteomics, pioneered in the author's laboratory. The importance and significance of the research emanating from the Butterfield laboratory rest on the paradigm shift of thinking regarding the roles of oxidative stress and resulting damage to key proteins and biochemical pathways in the pathogenesis and progression of AD. Predictions of future research directions also are presented. Given the enormous financial and personal burden placed upon citizens (and governments) of the US from AD, and the surety that the number of AD patients will greatly increase over the next 20-30 years, greater understanding of the molecular basis of pathogenesis and progression of AD is essential. Our laboratory is privileged to have contributed to better understanding of AD and provided rationales to identify effective therapeutic targets for this devastating dementing disorder.

11 Review mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia. 2018

Di Domenico, Fabio / Tramutola, Antonella / Foppoli, Cesira / Head, Elizabeth / Perluigi, Marzia / Butterfield, D Allan. ·Department of Biochemical Sciences, Sapienza University of Rome, Rome 00185, Italy. · Sanders-Brown Center on Aging and Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA. · Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506 USA. Electronic address: dabcns@uky.edu. ·Free Radic Biol Med · Pubmed #28807816.

ABSTRACT: The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studies linked the alterations of mTOR pathway to age-dependent cognitive decline, pathogenesis of Alzheimer disease (AD) and AD-like dementia in Down syndrome (DS). DS is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of AD in DS is complex and involves impaired mitochondrial function, defects in neurogenesis, increased oxidative stress, altered proteostasis and autophagy networks as a result of triplication of chromosome 21(chr 21). The chr21 gene products are considered a principal neuropathogenic moiety in DS. Several genes involved respectively in the formation of senile plaques and neurofibrillary tangles (NFT), two main pathological hallmarks of AD, are mapped on chr21. Further, in subjects with DS the activation of mTOR signaling contributes to Aβ generation and the formation of NFT. This review discusses recent research highlighting the complex role of mTOR associated with the presence of two hallmarks of AD pathology, senile plaques (composed mostly of fibrillar Aß peptides), and NFT (composed mostly of hyperphosphorylated tau protein). Oxidative stress, associated with chr21-related Aβ and mitochondrial alterations, may significantly contribute to this linkage of mTOR to AD-like neuropathology in DS.

12 Review HNE-modified proteins in Down syndrome: Involvement in development of Alzheimer disease neuropathology. 2017

Barone, Eugenio / Head, Elizabeth / Butterfield, D Allan / Perluigi, Marzia. ·Department of Biochemical Sciences, Sapienza University of Rome, Italy; Universidad Autónoma de Chile, Instituto de Ciencias Biomédicas, Facultad de Salud, Avenida Pedro de Valdivia 425, Providencia, Santiago, Chile. · Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA. · Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA. · Department of Biochemical Sciences, Sapienza University of Rome, Italy. Electronic address: marzia.perluigi@uniroma1.it. ·Free Radic Biol Med · Pubmed #27838436.

ABSTRACT: Down syndrome (DS), trisomy of chromosome 21, is the most common genetic form of intellectual disability. The neuropathology of DS involves multiple molecular mechanisms, similar to AD, including the deposition of beta-amyloid (Aβ) into senile plaques and tau hyperphosphorylationg in neurofibrillary tangles. Interestingly, many genes encoded by chromosome 21, in addition to being primarily linked to amyloid-beta peptide (Aβ) pathology, are responsible for increased oxidative stress (OS) conditions that also result as a consequence of reduced antioxidant system efficiency. However, redox homeostasis is disturbed by overproduction of Aβ, which accumulates into plaques across the lifespan in DS as well as in AD, thus generating a vicious cycle that amplifies OS-induced intracellular changes. The present review describes the current literature that demonstrates the accumulation of oxidative damage in DS with a focus on the lipid peroxidation by-product, 4-hydroxy-2-nonenal (HNE). HNE reacts with proteins and can irreversibly impair their functions. We suggest that among different post-translational modifications, HNE-adducts on proteins accumulate in DS brain and play a crucial role in causing the impairment of glucose metabolism, neuronal trafficking, protein quality control and antioxidant response. We hypothesize that dysfunction of these specific pathways contribute to accelerated neurodegeneration associated with AD neuropathology.

13 Review Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders. 2017

Di Domenico, Fabio / Tramutola, Antonella / Butterfield, D Allan. ·Department of Biochemical Sciences, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy. · Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA. Electronic address: dabcns@uky.edu. ·Free Radic Biol Med · Pubmed #27789292.

ABSTRACT: Oxidative stress is involved in various and numerous pathological states including several age-related neurodegenerative diseases. Peroxidation of the membrane lipid bilayer is one of the major sources of free radical-mediated injury that directly damages neurons causing increased membrane rigidity, decreased activity of membrane-bound enzymes, impairment of membrane receptors and altered membrane permeability and eventual cell death. Moreover, the peroxidation of polyunsaturated fatty acids leads to the formation of aldehydes, which can act as toxic by-products. One of the most abundant and cytotoxic lipid -derived aldehydes is 4-hydroxy 2-nonenal (HNE). HNE toxicity is mainly due to the alterations of cell functions by the formation of covalent adducts of HNE with proteins. A key marker of lipid peroxidation, HNE-protein adducts, were found to be elevated in brain tissues and body fluids of Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis subjects and/or models of the respective age-related neurodegenerative diseases. Although only a few proteins were identified as common targets of HNE modification across all these listed disorders, a high overlap of these proteins occurs concerning the alteration of common pathways, such as glucose metabolism or mitochondrial function that are known to contribute to cognitive decline. Within this context, despite the different etiological and pathological mechanisms that lead to the onset of different neurodegenerative diseases, the formation of HNE-protein adducts might represent the shared leit-motif, which aggravates brain damage contributing to disease specific clinical presentation and decline in cognitive performance observed in each case.

14 Review Modulation of GLP-1 signaling as a novel therapeutic approach in the treatment of Alzheimer's disease pathology. 2017

Tramutola, Antonella / Arena, Andrea / Cini, Chiara / Butterfield, D Allan / Barone, Eugenio. ·a Department of Biochemical Sciences 'A. Rossi-Fanelli' , Sapienza University of Rome , Roma , Italy. · b Department of Chemistry and Sanders-Brown Center on Aging , University of Kentucky , Lexington , KY , USA. · c Universidad Autónoma de Chile, Instituto de Ciencias Biomédicas , Facultad de Salud , Santiago , Chile. ·Expert Rev Neurother · Pubmed #27715341.

ABSTRACT: INTRODUCTION: Clinical studies suggest a link between peripheral insulin resistance and cognitive dysfunction. Post-mortem analyses of Alzheimer disease (AD) subjects revealed insulin resistance in the brain, suggesting a role of this condition in cognitive deficits observed in AD. In this review, we focus on the glucagon-like peptide-1 (GLP-1) signaling pathway, whose role in the brain is collecting increasing attention because of its association with insulin signaling activation. Areas covered: The role of GLP-1-mediated effects in the brain and how they are affected along the progression of AD pathology is discussed. Furthermore, we provide a comprehensive discussion about the use of GLP-1 mimetics drugs, which have been developed as a treatment for T2DM but seem to possess a number of other physiological properties, including neuroprotective and anti-inflammatory effects, that may be useful to slow AD progression. Expert commentary: The repurposing of antidiabetic drugs for the modulation of brain insulin resistance in AD appears to be of great interest. The beneficial effects on synaptogenesis, neurogenesis, and cell repair as well as the reduction of the chronic inflammatory response, and most importantly the reduction of amyloid plaques in the brain indicate that these drugs have promise as novel treatments for AD.

15 Review Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology. 2017

Tramutola, Antonella / Di Domenico, Fabio / Barone, Eugenio / Arena, Andrea / Giorgi, Alessandra / di Francesco, Laura / Schininà, Maria Eugenia / Coccia, Raffaella / Head, Elizabeth / Butterfield, D Allan / Perluigi, Marzia. ·1 Department of Biochemical Sciences, Sapienza University of Rome , Italy, Rome. · 2 Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky. · 3 Department of Pharmacology and Nutritional Sciences, University of Kentucky , Lexington, Kentucky. · 4 Department of Chemistry, University of Kentucky , Lexington, Kentucky. ·Antioxid Redox Signal · Pubmed #27627691.

ABSTRACT: AIMS: Among the putative mechanisms proposed to be common factors in Down syndrome (DS) and Alzheimer's disease (AD) neuropathology, deficits in protein quality control (PQC) have emerged as a unifying mechanism of neurodegeneration. Considering that disturbance of protein degradation systems is present in DS and that oxidized/misfolded proteins require polyubiquitinylation for degradation via the ubiquitin proteasome system, this study investigated if dysregulation of protein polyubiquitinylation is associated with AD neurodegeneration in DS. RESULTS: Postmortem brains from DS cases before and after development of AD neuropathology and age-matched controls were analyzed. By selectively isolating polyubiquitinated proteins, we were able to identify specific proteins with an altered pattern of polyubiquitinylation as a function of age. Interestingly, we found that oxidation is coupled with polyubiquitinylation for most proteins mainly involved in PQC and energy metabolism. INNOVATION: This is the first study showing alteration of the polyubiquitinylation profile as a function of aging in DS brain compared with healthy controls. Understanding the onset of the altered ubiquitome profile in DS brain may contribute to identification of key molecular regulators of age-associated cognitive decline. CONCLUSIONS: Disturbance of the polyubiquitinylation machinery may be a key feature of aging and neurodegeneration. In DS, age-associated deficits of the proteolytic system may further exacerbate the accumulation of oxidized/misfolded/polyubiquitinated proteins, which is not efficiently degraded and may become harmful to neurons and contribute to AD neuropathology. Antioxid. Redox Signal. 26, 280-298.

16 Review The Triangle of Death in Alzheimer's Disease Brain: The Aberrant Cross-Talk Among Energy Metabolism, Mammalian Target of Rapamycin Signaling, and Protein Homeostasis Revealed by Redox Proteomics. 2017

Di Domenico, Fabio / Barone, Eugenio / Perluigi, Marzia / Butterfield, D Allan. ·1 Department of Biochemical Sciences, Sapienza University of Rome , Rome, Italy . · 2 Facultad de Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile , Santiago, Chile . · 3 Department of Chemistry, Sanders-Brown Center of Aging, University of Kentucky , Lexington, Kentucky. ·Antioxid Redox Signal · Pubmed #27626216.

ABSTRACT: SIGNIFICANCE: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and represents one of the most disabling conditions. AD shares many features in common with systemic insulin resistance diseases, suggesting that it can be considered as a metabolic disease, characterized by reduced insulin-stimulated growth and survival signaling, increased oxidative stress (OS), proinflammatory cytokine activation, mitochondrial dysfunction, impaired energy metabolism, and altered protein homeostasis. Recent Advances: Reduced glucose utilization and energy metabolism in AD have been associated with the buildup of amyloid-β peptide and hyperphosphorylated tau, increased OS, and the accumulation of unfolded/misfolded proteins. Mammalian target of rapamycin (mTOR), which is aberrantly activated in AD since early stages, plays a key role during AD neurodegeneration by, on one side, inhibiting insulin signaling as a negative feedback mechanism and, on the other side, regulating protein homeostasis (synthesis/clearance). CRITICAL ISSUES: It is likely that the concomitant and mutual alterations of energy metabolism-mTOR signaling-protein homeostasis might represent a self-sustaining triangle of harmful events that trigger the degeneration and death of neurons and the development and progression of AD. Intriguingly, the altered cross-talk between the components of such a triangle of death, beyond altering the redox homeostasis of the neuron, is further exacerbated by increased levels of OS that target and impair key components of the pathways involved. Redox proteomic studies in human samples and animal models of AD-like dementia led to identification of oxidatively modified components of the pathways composing the triangle of death, therefore revealing the crucial role of OS in fueling this aberrant vicious cycle. FUTURE DIRECTIONS: The identification of compounds able to restore the function of the pathways targeted by oxidative damage might represent a valuable therapeutic approach to slow or delay AD. Antioxid. Redox Signal. 26, 364-387.

17 Review Oxidative stress, protein modification and Alzheimer disease. 2017

Tramutola, A / Lanzillotta, C / Perluigi, M / Butterfield, D Allan. ·Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy. · Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA. Electronic address: dabcns@uky.edu. ·Brain Res Bull · Pubmed #27316747.

ABSTRACT: Alzheimer disease (AD) is a progressive neurodegenerative disease that affects the elderly population with complex etiology. Many hypotheses have been proposed to explain different causes of AD, but the exact mechanisms remain unclear. In this review, we focus attention on the oxidative-stress hypothesis of neurodegeneration and we discuss redox proteomics approaches to analyze post-mortem human brain from AD brain. Collectively, these studies have provided valuable insights into the molecular mechanisms involved both in the pathogenesis and progression of AD, demonstrating the impairment of numerous cellular processes such as energy production, cellular structure, signal transduction, synaptic function, mitochondrial function, cell cycle progression, and degradative systems. Each of these cellular functions normally contributes to maintain healthy neuronal homeostasis, so the deregulation of one or more of these functions could contribute to the pathology and clinical presentation of AD. In particular, we discuss the evidence demonstrating the oxidation/dysfunction of a number of enzymes specifically involved in energy metabolism that support the view that reduced glucose metabolism and loss of ATP are crucial events triggering neurodegeneration and progression of AD.

18 Review Aberrant protein phosphorylation in Alzheimer disease brain disturbs pro-survival and cell death pathways. 2016

Perluigi, M / Barone, E / Di Domenico, F / Butterfield, D A. ·Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy. · Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy; Universidad Autónoma de Chile, Instituto de Ciencias Biomédicas, Facultad de Salud, Providencia, Santiago, Chile. · Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA. Electronic address: dabcns@uky.edu. ·Biochim Biophys Acta · Pubmed #27425034.

ABSTRACT: Protein phosphorylation of serine, threonine, and tyrosine residues is one of the most prevalent post-translational modifications fundamental in mediating diverse cellular functions in living cells. Aberrant protein phosphorylation is currently recognized as a critical step in the pathogenesis and progression of Alzheimer disease (AD). Changes in the pattern of protein phosphorylation of different brain regions are suggested to promote AD transition from a presymptomatic to a symptomatic state in response to accumulating amyloid β-peptide (Aβ). Several experimental approaches have been utilized to profile alteration of protein phosphorylation in the brain, including proteomics. Among central pathways regulated by kinases/phosphatases those involved in the activation/inhibition of both pro survival and cell death pathways play a central role in AD pathology. We discuss in detail how aberrant phosphorylation could contribute to dysregulate p53 activity and insulin-mediated signaling. Taken together these results highlight that targeted therapeutic intervention, which can restore phosphorylation homeostasis, either acting on kinases and phosphatases, conceivably may prove to be beneficial to prevent or slow the development and progression of AD.

19 Review It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease. 2016

Tramutola, Antonella / Di Domenico, Fabio / Barone, Eugenio / Perluigi, Marzia / Butterfield, D Allan. ·Department of Biochemical Sciences, Sapienza University of Rome, Italy. · Department of Biochemical Sciences, Sapienza University of Rome, Italy; Facultad de Salud, Universidad Autónoma de Chile, Instituto de Ciencias Biomédicas, Providencia, Santiago, Chile. · Department of Chemistry, Sanders-Brown Center of Aging, University of Kentucky, Lexington, KY 40506, USA. ·Oxid Med Cell Longev · Pubmed #26881020.

ABSTRACT: Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of "aberrant" proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity.

20 Review Clinical implications from proteomic studies in neurodegenerative diseases: lessons from mitochondrial proteins. 2016

Butterfield, D Allan / Palmieri, Erika M / Castegna, Alessandra. ·a Department of Chemistry, and Sanders-Brown Center on Aging , University of Kentucky , Lexington , KY , USA. · b Department of Biosciences, Biotechnologies and Biopharmaceutics , University of Bari 'Aldo Moro' , Bari , Italy. ·Expert Rev Proteomics · Pubmed #26837425.

ABSTRACT: Mitochondria play a key role in eukaryotic cells, being mediators of energy, biosynthetic and regulatory requirements of these cells. Emerging proteomics techniques have allowed scientists to obtain the differentially expressed proteome or the proteomic redox status in mitochondria. This has unmasked the diversity of proteins with respect to subcellular location, expression and interactions. Mitochondria have become a research 'hot spot' in subcellular proteomics, leading to identification of candidate clinical targets in neurodegenerative diseases in which mitochondria are known to play pathological roles. The extensive efforts to rapidly obtain differentially expressed proteomes and unravel the redox proteomic status in mitochondria have yielded clinical insights into the neuropathological mechanisms of disease, identification of disease early stage and evaluation of disease progression. Although current technical limitations hamper full exploitation of the mitochondrial proteome in neurosciences, future advances are predicted to provide identification of specific therapeutic targets for neurodegenerative disorders.

21 Review Vitamin D deficiency and Alzheimer disease: Common links. 2015

Keeney, Jeriel T / Butterfield, D Allan. ·College of Human Medicine, Translational Science and Molecular Medicine, Michigan State University, Van Andel Institute, Grand Rapids, MI 49503, USA. Electronic address: keeneyj2@msu.edu. · Department of Chemistry and Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA. Electronic address: dabcns@email.uky.edu. ·Neurobiol Dis · Pubmed #26160191.

ABSTRACT: Vitamin D (VitD) deficiency is a worldwide epidemic with estimates of 1 billion affected. In addition to the classically known roles of VitD in calcium regulation and bone health, recent studies demonstrated VitD to be an essential/vital neurosteroid hormone playing a wide variety of essential protective and regulatory roles in the brain. This paper reviews much of the mounting evidence of the detrimental effects of VitD deficiency on the brain and the association of many of these common links with Alzheimer's disease (AD). We also discuss the beneficial effects seen from VitD supplementation. Based on this accumulation of studies, we propose that VitD screening should be performed at least in those individuals at risk for VitD deficiency and AD. With appropriate medical counsel, those found to be VitD deficient should be considered for appropriate supplementation.

22 Review Oxidative stress in Alzheimer disease and mild cognitive impairment: evidence from human data provided by redox proteomics. 2015

Swomley, Aaron M / Butterfield, D Allan. ·Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40506-0055, USA. · Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40506-0055, USA. dabcns@pop.uky.edu. ·Arch Toxicol · Pubmed #26126631.

ABSTRACT: Alzheimer disease (AD) is a neurodegenerative disease with many known pathological features, yet there is still much debate into the exact cause and mechanisms for progression of this degenerative disorder. The amyloid-beta (Aβ)-induced oxidative stress hypothesis postulates that it is the oligomeric Aβ that inserts into membrane systems to initiate much of the oxidative stress observed in brain during the progression of the disease. In order to study the effects of oxidative stress on tissue from patients with AD and amnestic mild cognitive impairment (MCI), we have developed a method called redox proteomics that identifies specific brain proteins found to be selectively oxidized. Here, we discuss experimental findings of oxidatively modified proteins involved in three key cellular processes implicated in the pathogenesis of AD progression: energy metabolism, cell signaling and neurotransmission, as well as the proteasomal degradation pathways and antioxidant response systems. These proteomics studies conducted by our laboratory and others in the field shed light on the molecular changes imposed on the cells of AD and MCI brain, through the deregulated increase in oxidative/nitrosative stress inflicted by Aβ and mitochondrial dysfunction.

23 Review mTOR signaling in aging and neurodegeneration: At the crossroad between metabolism dysfunction and impairment of autophagy. 2015

Perluigi, Marzia / Di Domenico, Fabio / Butterfield, D Allan. ·Department of Biochemical Sciences, Sapienza University of Rome, Italy. Electronic address: Marzia.perluigi@uniroma1.it. · Department of Biochemical Sciences, Sapienza University of Rome, Italy. · Sanders-Brown Centre of Aging, University of Kentucky, Lexington KY, USA; Department of Chemistry, University of Kentucky, Lexington KY, USA. ·Neurobiol Dis · Pubmed #25796566.

ABSTRACT: Compelling evidence indicates that the mammalian target of rapamycin (mTOR) signaling pathway is involved in cellular senescence, organismal aging and age-dependent diseases. mTOR is a conserved serine/threonine kinase that is known to be part of two different protein complexes: mTORC1 and mTORC2, which differ in some components and in upstream and downstream signalling. In multicellular organisms, mTOR regulates cell growth and metabolism in response to nutrients, growth factors and cellular energy conditions. Growing studies highlight that disturbance in mTOR signalling in the brain affects multiple pathways including glucose metabolism, energy production, mitochondrial function, cell growth and autophagy. All these events are key players in age-related cognitive decline such as development of Alzheimer disease (AD). The current review discusses the main regulatory roles of mTOR signalling in the brain, in particular focusing on autophagy, glucose metabolism and mitochondrial functions. Targeting mTOR in the CNS can offer new prospective for drug discovery; however further studies are needed for a comprehensive understanding of mTOR, which lies at the crossroads of multiple signals involved in AD etiology and pathogenesis.

24 Review Insulin resistance in Alzheimer disease: Is heme oxygenase-1 an Achille's heel? 2015

Barone, Eugenio / Butterfield, D Allan. ·Department of Biochemical Sciences, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy. · Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA. Electronic address: dabcns@uky.edu. ·Neurobiol Dis · Pubmed #25731746.

ABSTRACT: Insulin resistance, clinically defined as the inability of insulin to increase glucose uptake and utilization, has been found to be associated with the progression of Alzheimer disease (AD). Indeed, postmortem AD brain shows all the signs of insulin resistance including: (i) reduced brain insulin receptor (IR) sensitivity, (ii) hypophosphorylation of the insulin receptor and downstream second messengers such as IRS-1, and (iii) attenuated insulin and insulin growth factor (IGF)-1 receptor expression. However, the exact mechanisms driving insulin resistance have not been completely elucidated. Quite recently, the levels of the peripheral inducible isoform of heme oxygenase (HO-1), a well-known protein up-regulated during cell stress response, were proposed to be among the strongest positive predictors of metabolic disease, including insulin resistance. Because our group previously reported on levels, activation state and oxidative stress-induced post-translational modifications of HO-1 in AD brain and our ongoing studies to better elucidate the role of HO-1 in insulin resistance-associated AD pathology, the aim of this review is to provide reader with a critical analysis on new aspects of the interplay between HO-1 and insulin resistance and on how the available lines of evidence could be useful for further comprehension of processes in AD brain.

25 Review Strategy to reduce free radical species in Alzheimer's disease: an update of selected antioxidants. 2015

Di Domenico, Fabio / Barone, Eugenio / Perluigi, Marzia / Butterfield, D Allan. ·Department of Biochemical Sciences, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy. ·Expert Rev Neurother · Pubmed #25243342.

ABSTRACT: Alzheimer's disease (AD), characterized by progressive loss of memory, language, reasoning and other cognitive functions, including dementia, is characterized pathologically by the presence of senile plaques, neurofibrillary tangles and synapse loss. Increased oxidative/nitrosative stress, decreased antioxidants, mitochondrial damage and other factors play major roles in the development and progression of AD. Strategies to reduce pro-oxidant species to ameliorate AD pathology have been proposed with mixed results. In this review, we focus on the most recent in vitro and in vivo antioxidant approaches for removing oxidant species with relevance to AD, including N-acetyl-l-cysteine, vitamin D, vitamin E, ferulic acid, tricyclodecan-9-yl-xanthogenate, selenium and melatonin as therapeutic stratagems in AD management. In addition, we reviewed the most effective mitochondria targeted antioxidants such as coenzyme Q10 and lipoic acid. We suggest the use of multitargeted approaches by formulas containing one or more antioxidant compounds may be more promising than single-agent approaches.

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