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 (FAD), Preclinical AD (PCAD), Mild Cognitive Impairment (MCI), Early AD (EAD), Late AD (LAD), 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.
Keywords: Redox proteomics, Alzheimer disease, amyloid β-peptide, oxidative stress
Graphical Abstract
In this review we discuss how redox proteomics provided insights into how Aβ(1–42)-mediated cell death in Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI), and in in vitro and in vivo models thereof, is initiated by lipid peroxidation. Oligomeric Aβ(1–42) embeds in the lipid bilayer inducing lipid peroxidation, leading to reactive 4-hydroxy-2-nonenal (HNE). HNE covalently binds Cys, His, and Lys residues on proteins by Michael addition, changing the proteins’ conformation and decreasing their function. Key processes in brain that are damaged and dysfunctional as a result of Aβ(1–42)-mediated HNE modification identified by redox proteomics are glucose metabolism, synaptic plasticity, synaptic glutamate clearance, and proteostasis, ultimately leading to neuronal death.
Alzheimer Disease (AD) is a neurodegenerative disorder characterized by changes in brain chemistry associated with cognitive decline and aging. AD is the most common cause of dementia (Wilson et al. 2012; Barker et al. 2002) and is currently the 6th leading cause of death in the United States (US). It is estimated that there are over 5.7 million Americans currently living with AD and of those 5.5 million are age 65 or older; however, with the aging baby boomer population, it is projected that the number of Americans age 65 or older living with AD will increase to 7.1 million by 2025 and to 13.8 million by 2050. Additionally, due to medical advances, it is also expected that the population of Americans living beyond age 85 will increase subsequently increasing the population most at risk of developing AD. Given that no definitive cause, treatment, preventative, or cure exists for AD, the US is facing a growing public health crisis as national costs associated with AD are projected to increase from $277 billion to $1.1 trillion by 2050 (Alzheimer’s Association 2018).
One percent or fewer of AD cases are familial, due to inherited genetic mutations (Bekris et al. 2010), meaning that the overwhelming majority of cases are sporadic and likely due to a concert of multiple factors. The greatest risk factors for developing AD include age, family history, and apolipoprotein E (ApoE) genotype. Three allelic forms of ApoE exist: ε2, ε3, and ε4. ε3 is the most common form followed by ε4, and finally ε2 (Mahley and Rall 2000). ε4 is associated with an increased risk of developing AD with heterozygotes having a three times greater risk and homozygotes having an eight to twelve times greater risk than those homozygous in ε3 (Loy et al. 2014; Holtzman et al. 2012). While the ApoE ε4 is associated with an increased risk of developing AD, it does not guarantee that one will develop AD (Chouraki et al. 2014). Those with the ε2 form have a decreased risk compared to those with the ε3 form (Loy et al. 2014; Holtzman et al. 2012). Collectively, age, family history, and genetics are factors beyond our control; however, there are also a number of risk factors that can be influenced by lifestyle modifications over which we do have control. Obesity (Rönnemaa et al. 2011; Loef et al. 2013; Anstey et al. 2011; Gottesman et al. 2017a), diabetes (Wu et al. 2008; Gudala et al. 2013; Vagelatos et al. 2013; Reitz et al. 2011), impaired glucose metabolism (Rönnemaa et al. 2011; Crane et al. 2013), hyperlipidemia (Solomon et al. 2009; Meng et al. 2014), and hypertension (Launer et al. 2000; Ninomiya et al. 2011; Debette et al. 2011; Livingston et al. 2017; Gottesman et al. 2017b) are all associated with increased risk of developing AD. Increased physical activity (Willis et al. 2012; Tan et al. 2017; Wiley et al. 2016; Stephen et al. 2017; Blondell et al. 2014; Koscak 2017) and consuming a heart-healthy diet are associated with a decreased risk of developing AD (Barberger-Gateau et al. 2007; Hardman et al. 2016; Lourida et al. 2013; Morris et al. 2015a; Morris et al. 2015b; Féart et al. 2010; Solfrizzi et al. 2011). Recent studies indicate that brain changes associated with AD may begin 20 or more years before the onset of cognitive symptoms (Villemagne et al. 2013; Reiman et al. 2012; Jack et al. 2009; Bateman et al. 2012) suggesting that lifestyle interventions that decrease midlife obesity, diabetes, hypertension, and high cholesterol could potentially reduce the prevalence, or delay the onset, of Alzheimer’s disease. Delay of onset by 5 years is estimated to reduce costs by 33 (Alzheimer’s Association 2015) to 39 percent (Zissimopoulos et al. 2014).
Extraneuronal deposition of amyloid beta-peptide (Aβ), measured by positron emission tomography (PET), precedes (Aizenstein et al. 2008; Mintun et al. 2006; Rowe et al. 2010) and positively correlates with cognitive decline and cerebral atrophy (Villemagne et al. 2013). Aβ is a 40- to 42-amino acid peptide derived from amyloid precursor protein (APP) by the concerted proteolytic action of β-secretase at the amino-terminus and γ-secretase at the carboxy-terminus. Aβ(1–42), which comprises the majority of Aβ found in senile plaques in AD brain (Selkoe 2001), is the more toxic of these species (Butterfield 1997; Butterfield et al. 2002; Copani et al. 1991; Walsh and Teplow 2012) with several studies indicating that, rather than fibrils, small soluble oligomers are the toxic form of Aβ (Drake et al. 2003; Lambert et al. 2001; Oda et al. 1995; Walsh et al. 1999). Genetic mutations that lead to familial AD (FAD) involve the genes encoding presenilin-1 or presenilin-2, which comprise the catalytic element of γ-secretase, or APP and all subsequently increase the production of Aβ(1–42) (Selkoe 2001; Goate and Hardy 2012; Jarrett et al. 1993; Scheuner et al. 1996). Down Syndrome (DS) lends further genetic evidence as to the importance of APP and the consequential role of Aβ in AD pathogenesis. DS patients have three copies of chromosome 21 which contains the gene encoding APP resulting in increased production of Aβ (Beyreuther et al. 1993) which initially accumulates intracellularly, but then decreases intracellularly as extracellular Aβ deposits form (Gyure et al. 2001; Mori et al. 2002). If DS patients live long enough, they develop brain pathology and cognitive symptoms indistinguishable from AD (Wisniewski et al. 1985; Lott and Head 2005; Lott and Dierssen 2010).
Progression of AD can be viewed as a continuous spectrum consisting of four stages: preclinical AD (PCAD), mild cognitive impairment (MCI), early AD (EAD), and late-stage AD (LAD). IN PCAD, the patient is fully functional, but brain pathology changes – which can be divided into three stages – have begun to develop unbeknownst to the patient (Dubois et al. 2016; Vos et al. 2013; Pietrzak et al. 2015; Small et al. 2001; Sperling et al. 2011; Vlassenko et al. 2012). Stage 1 is classified by the presence of abnormal Aβ biomarkers, stage 2 is classified by the presence of abnormal Aβ biomarkers and neuronal injury, and stage 3 is an extension of stage 2 in which subtle cognitive changes are present (Sperling et al. 2011). MCI represents the transition between PCAD and EAD in which cognitive decline is noticeable but does not interfere with activities of daily living. MCI is further subdivided into amnestic MCI (aMCI) and non-amnestic MCI with aMCI having a higher conversion rate to AD (Kelley and Petersen 2007; Petersen 2000, 2004). EAD and LAD are marked by noticeable and progressive cognitive decline and behavioral changes that significantly impact the ability of the patient to carry out everyday functions. Imaging studies document progressive neuropathology and neurodegeneration as the disease advances from EAD into LAD (Drayer et al. 1985; Farrow et al. 2007; Jack et al. 1999, 2018; Rowe et al. 2010; Villemagne et al. 2013).
Elevated oxidative stress is implicated in the pathogenesis of AD (Butterfield et al. 2013; Swomley and Butterfield 2015) and is also detected in DS brain (Cenini et al. 2012; Jovanovic et al. 1998; Perluigi and Butterfield 2011, 2012). Aβ(1–42) induces oxidative stress in vitro and in vivo (Hensley et al. 1994; Butterfield et al. 1999; Butterfield and Boyd-Kimball 2004, 2018; Sultana et al. 2009) and, in AD brain. There are many hypotheses regarding the mechanism by which Aβ(1–42)-mediated oxidative stress plays a causative role in the progression of AD (Cheignon et al. 2018); however, our laboratory proposed that oligomers of Aβ(1–42) insert into the bilayer initiating lipid peroxidation (Butterfield and Lauderback 2002; Butterfield et al. 2001; Mark et al. 1997; Markesbery 1997; Mattson 1997) and the increased protein, lipid, DNA, and RNA oxidation observed in AD brain (Butterfield and Lauderback 2002; Butterfield and Stadtman 1997; Smith et al. 1997; Hensley et al.1995; Markesbery and Lovell 1998; Zhang et al. 1994; Mecocci et al. 1994; Gabbita et al. 1998; Shan and Lin 2006; Ding et al. 2006; Butterfield and Boyd-Kimball, 2018). Redox proteomics studies have allowed insight into the specific proteins susceptible to oxidation. Biomarkers of oxidative modification include protein carbonyls and the lipid peroxidation by-product, 4-hydroxy-2-trans-nonenal (HNE), and a marker of nitration, 3-nitrotyrosine (3-NT), which have been the foci of most redox proteomics analyses relevant to AD to date (Subramaniam et al. 1997; Butterfield and Perluigi 2017; Swomley et al. 2014; Sultana and Butterfield 2009, 2011; Sultana et al. 2009). Such irreversible oxidative protein modifications induced by Aβ(1–42) initiate conformation changes resulting in altered or lost function with consequences toward disease progression (Butterfield et al. 2007; Butterfield and Boyd-Kimball 2018). Reversible oxidative modifications, including S-nitrosylation (Nakamura et al. 2013) and cysteine oxidation (Gu and Robinson 2016), may also provide insights into pathogenesis; however, the focus of this review is irreversible oxidative modifications associated with Aβ(1–42) indexed by protein carbonyls, HNE and 3-NT as we summarize our current knowledge of Aβ(1–42)-induced protein oxidation in vitro and in vivo as evidenced by redox proteomics. Here, we first highlight the proteins identified by redox proteomics as oxidatively modified in these models, relate these same proteins that also are oxidized in aMCI and AD brain, and then discuss the implications of such modifications in the context of our current knowledge of AD.
In vitro Aβ(1–42)-induced protein oxidation
Currently, redox proteomics studies of the in vitro effects of Aβ(1–42) have focused solely on protein carbonylation (Table 1). In cortical synaptosomes incubated with Aβ(1–42), β-actin, glial fibrillary acid protein (GFAP), and dihydropyrimidinase-related protein-2 (DRP-2 also called collapsin response mediated protein-2, CRMP-2) were found to be significantly carbonylated (Boyd-Kimball et al. 2005a); however, in primary neuronal culture incubated with Aβ(1–42) 14-3-3ζ, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PK), and malate dehydrogenase (MDH) were found to be increasing carbonylated (Boyd-Kimball et al. 2005b; Sultana et al. 2006d). Proteins identified as oxidized by Aβ(1–42) in vitro are consistent with proteins identified to be oxidized in AD and aMCI brain (Castegna et al. 2002a,b, 2003; Aksenov et al. 2001; Sultana et al. 2006a,c, 2007; Butterfield et al. 2006a; Reed et al. 2008).
Table 1:
Aβ(1–42)-Induced Carbonylated Proteins in vitro
| Function | Protein | Model | References |
|---|---|---|---|
| Energy Metabolism | Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) | primary neuronal culture | Boyd-Kimball et al. 2005b; Sultana et al. 2006d |
| Malate dehydrogenase (MDH) | primary neuronal culture | Sultana et al. 2006d | |
| Pyruvate kinase (PK) | primary neuronal culture | Sultana et al. 2006d | |
| Synaptic plasticity, vesicle-mediated transport, and cell structure | Dihydropyrimidinase-related protein 2 (DRP-2) | cortical synaptosomes | Boyd-Kimball et al. 2005a |
| β-actin | cortical synaptosomes | Boyd-Kimball et al. 2005a | |
| Neuroinflammation | Glial fibrillary acidic protein (GFAP) | cortical synaptosomes | Boyd-Kimball et al. 2005a |
| Signal transduction | 14-3-3ζ | primary neuronal culture | Boyd-Kimball et al. 2005b; Sultana et al. 2006d |
In vivo Aβ(1–42)-induced protein oxidation: Models of Alzheimer’s Disease
Various models of the in vivo effects of Aβ(1–42) have been studied using redox proteomics (Table 2). One such model includes the intracerebral ventricular (ICV) injection of Aβ(1–42) into the nucleus basalis magnocellularis (NBM) of 3-month-old male Wistar rats. Seven days post-injection, 14-3-3ζ and chaperonin 60 (HSP60) were found to be significantly carbonylated in the NBM. Notably, this modeled also showed that the oxidative damage induced by Aβ(1–42) could spread beyond the site of injection resulting in the significant carbonylation of α- and β-tubulin and glutamine synthetase (GS) in the cortex, and 14-3-3ζ, β-synuclein, pyruvate dehydrogenase (PDH), GAPDH, and phosphoglycerate mutase 1 (PGM1) in the hippocampus (Boyd-Kimball et al. 2005c).
Table 2:
Aβ(1–42)-Induced Carbonylated Proteins in vivo
| Function | Protein | Model | Tissue | References |
|---|---|---|---|---|
| Antioxidants and Cellular Detoxification Defenses | Glutathione S-Transferase | Canineb | -- | Opii et al. 2008 |
| C. elegansb | -- | Boyd-Kimball et al. 2006 | ||
| Adenosine kinase | C. elegansb | -- | Boyd-Kimball et al. 2006 | |
| Arginine kinase | C. elegansb | -- | Boyd-Kimball et al. 2006 | |
| Glutamate dehydrogenase | Canineb | -- | Opii et al. 2008 | |
| Lipid binding protein | C. elegansb | -- | Boyd-Kimball et al. 2006 | |
| Energy Metabolism | acyl-CoA DH (medium chain) | C. elegansb | -- | Boyd-Kimball et al. 2006 |
| acyl-CoA DH (short-chain) | C. elegansb | -- | Boyd-Kimball et al. 2006 | |
| α-enolase | Canineb | -- | Opii et al. 2008 | |
| Glyceraldehyde-3-phosphate dehydrogenase | Canineb | -- | Opii et al. 2008 | |
| Wistar Rata | HP | Boyd-Kimball et al. 2005c | ||
| Malate dehydrogenase | C. elegansb | -- | Boyd-Kimball et al. 2006 | |
| Phosphoglycerate mutase 1 | Wistar Rata | HP | Boyd-Kimball et al. 2005c | |
| Pyruvate dehydrogenase (PDH) (lipoamide) | Wistar Rata | HP | Boyd-Kimball et al. 2005c | |
| Transketolase | C. elegansb | -- | Boyd-Kimball et al. 2006 | |
| Excitotoxicity | Glutamine Synthetase | Wistar Rata | Cortex | Boyd-Kimball et al. 2005c |
| Synaptic plasticity, vesicle-mediated transport, and cell structure | actin | C. elegansb | -- | Boyd-Kimball et al. 2006 |
| β-synuclein | Wistar Rata | HP | Boyd-Kimball et al. 2005c | |
| Fascin actin bundling protein | Canineb | -- | Opii et al. 2008 | |
| Myosin regulatory light chain | C. elegans | -- | Boyd-Kimball et al. 2006 | |
| Neurofilament triplet L | Canineb | -- | Opii et al. 2008 | |
| α-/β-tubulin | Wistar Rata | Cortex | Boyd-Kimball et al. 2005c | |
| Protein Synthesis | Elongation factor 1 γ | C. elegansb | -- | Boyd-Kimball et al. 2006 |
| Protein Folding and Degradation | HSP60 | Wistar Rata | NBM | Boyd-Kimball et al. 2005c |
| Proteasome α-subunit | C. elegansb | -- | Boyd-Kimball et al. 2006 | |
| Proteasome β-subunit | C. elegansb | -- | Boyd-Kimball et al. 2006 | |
| Signal Transduction | 14-3-3ζ | Wistar Rata | HP, NBM | Boyd-Kimball et al. 2005c |
Note: HP, hippocampus; NBM, nucleus basalis magnocellaris
ICV injection of Aβ(1–42) into the NBM with analysis 7 days post injection;
expresses Aβ(1–42) with human amino acid sequence.
C. elegans expressing human Aβ(1–42) were previously reported to cause elevated protein carbonyls correlated with aggregated Aβ(1–42) (Yatin et al. 1999). Subsequent studies used a mRNA surveillance system to degrade foreign mRNA at permissive (regular) growth temperatures. The non-permissive elevated growth temperature caused the surveillance system to be inactive, resulting in expression of Aβ(1–42) for any given time chosen by the experimenter. Return to permissive temperature stopped Aβ(1–42) expression. Expression of Aβ(1–42) for 24 h led to elevated oxidative damage (protein carbonyls) in the worm that was correlated with paralysis, since a muscle wall promoter was used to express Aβ(1–42), and there was absence of Aβ fibril formation, consistent with the notion that oligomers of Aβ(1–42) inserted into the muscle cell membranes led to oxidative stress (Drake et al. 2003). Redox proteomics analysis of this C. elegans strain identified both short and medium chain acyl-CoA dehydrogenase (acyl CoA DH), elongation factor 1 γ (Ef-1 γ), MDH, arginine kinase (AK), RACK1 ortholog, myosin regulatory light chain (MRLC), actin, adenosine kinase (ADK), lipid binding protein (LBP), transketolase (TK), proteasome α- and β-subunit, and glutathione-S-transferase (GST) to be significantly carbonylated (Boyd-Kimball et al. 2006).
The canine model of the aged beagle deposits Aβ(1–42) identical to the human amino acid sequence as a function of age (Miligram et al. 2004; Head 2013). Long-term administration of an antioxidant-rich diet and behavioral enrichment resulted in the significantly decreased carbonylation of glutamate dehydrogenase (GDH), GAPDH, α-enolase, neurofilament triplet L, GST P, and fascin actin bundling protein compared to age-matched control (Opii et al. 2008). These findings support a role for lifestyle intervention as a therapeutic approach to prevent or delay Aβ(1–42) induced oxidative stress.
Redox proteomics has also been utilized to analyze several transgenic or knock-in rodent models of AD including the APP/PS-1 double human mutant knock-in mouse (the APP/PS-1 mouse), the triple transgenic AD mouse (3×Tg-AD), the senescence accelerated mouse P8 (SAMP8), and the J20 mouse (Table 3). The APP/PS1 double human knock-in mouse is the APPNLh/NLh × PS-1P264L/P264L strain which expresses normal levels of human APP, but significantly increased levels of Aβ(1–42) prior to two months of age. Aβ deposition occurs by 6 months of age and increases linearly as a function of age (Flood et al. 2002) similar to Aβ solubility and deposition exhibited in human brain during the progression of AD (Murphy et al. 2007). This age-dependent increase in Aβ(1–42) production correlates with cognitive impairment (Bruce-Keller et al. 2011; Webster et al. 2013), oxidative stress (Abdul et al. 2008; Huang et al. 2010), decreased manganese superoxide dismutase (MnSOD or SOD2) activity and mitochondrial respiration (Anantharaman et al. 2006; Sompol et al. 2008), and loss of phospholipid asymmetry (Bader Lange et al. 2010). Redox proteomics was used to analyze the oxidative modification of proteins, as indexed by protein carbonyls, in the brain of APPNLh/NLh × PS-1P264L/P264L mice as a function of age compared to age-matched wild-type control. Proteins identified to be significantly oxidized can be broadly classified as structural, regulatory, synaptic, and involved in glucose metabolism. The structural protein β-actin was found to be significantly oxidized at 1 month and 15 months of age while the synaptic protein β-synuclein was found to be significantly oxidized at 12 months of age. The regulatory proteins identified were 14-3-3ζ/δ/γ and peptidylprolyl cis-trans isomerase-1 (Pin1). 14-3-3ζ/δ/γ was found to be significantly oxidized at 1, 9, 12, and 15 months, while Pin-1 was found to be significantly oxidized at 9, 12 and 15 months of age. α-enolase, pyruvate dehydrogenase E1 (PDH), and ATP synthase α-subunit – all proteins involved in generating cellular energy – were determined to be significantly oxidized. α-enolase was found to be significantly oxidized at 6, 9, 12, and 15 months and ATP synthase was found to be significantly oxidized at 12 and 15 months while PDH was found to be significantly oxidized only at 6 months of age (Sultana et al. 2011a).
Table 3:
Oxidatively Modified Proteins Identified in AD mouse models
| Function | Protein | Transgenic Mouse Model | Age (months) | Oxidative Modification | References |
|---|---|---|---|---|---|
| Cellular Redox Homeostasis and Detoxification Defense | Peroxiredoxin 2 (Prx2) | SAMP8a | 12 | C↓ | Poon et al. 2005 |
| Energy Metabolism | Aconitase | 3×Tg-AD | 3 | C↑ | Shen et al. 2015 |
| Aldolase | SAMP8a | 12 | C↓ | Poon et al. 2005 | |
| ATP Synthase | APP/PS1 KI | 12,15 | C↑ | Sultana et al. 2011a | |
| Creatine Kinase (CK) | SAMP8 | 12 | C↑ | Poon et al. 2004 | |
| α-enolase | APP/PS1 KI | 6,9,12,15 | C↑ | Sultana et al. 2011a | |
| 3×Tg-AD | 3 | C↑ | Shen et al. 2015 | ||
| SAMP8b | 12 | N↑ | Fiorini et al. 2013 | ||
| Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) | 3×Tg-AD | 3 | C↑ | Shen et al. 2015 | |
| Isocitrate dehydrogenase (IDH) | SAMP8b | 12 | N↑ | Fiorini et al. 2013 | |
| Lactate dehydrogenase (LDH) | SAMP8b | 12 | N↑ | Fiorini et al. 2013 | |
| SAMP8 | 12 | C↑ | Poon et al. 2004 | ||
| Malate dehydrogenase (MDH) | 3×Tg-AD | 3 | C↑ | Shen et al. 2015 | |
| Phosphoglycerate kinase (PGK) | 3×Tg-AD | 3 | C↑ | Shen et al. 2015 | |
| Pyruvate dehydrogenase (PDH) (E1) | APP/PS1 KI | 6 | C↑ | Sultana et al. 2011a | |
| Synaptic plasticity, vesicle-mediated transport and cell structure | β-synuclein | APP/PS1 KI | 12 | C↑ | Sultana et al. 2011a |
| Dihydropyrimidinase-related protein 1 (DRP-1) | SAMP8b | 12 | N↑ | Fiorini et al. 2013 | |
| Dihydropyrimidinase-related protein 2 (DRP-2) | SAMP8 | 12 | C↑ | Poon et al. 2004 | |
| SAMP8b | 12 | N↓ | Fiorini et al. 2013 | ||
| Dynamin-1 | SAMP8b | 12 | N↑ | Fiorini et al. 2013 | |
| Vesicle-fusing ATPase | SAMP8b | 12 | N↑ | Fiorini et al. 2013 | |
| Septin 11 | SAMP8b | 12 | N↑ | Fiorini et al. 2013 | |
| Neuropolypeptide h3 (PEBP1) | J20 | 9 | N↓ | Robinson et al. 2011 | |
| β-Actin | APP/PS1 KI | 1,15 | C↑ | Sultana et al. 2011a | |
| Actin related protein 2 | SAMP8b | 12 | N↑ | Fiorini et al. 2013 | |
| Coronin1A | SAMP8a | 12 | C↓ | Poon et al. 2005 | |
| Neurofilament light polypeptide | 3×Tg-AD | 3 | C↑ | Shen et al. 2015 | |
| α-Spectrin 2 | SAMP8 | 12 | C↑ | Poon et al. 2004 | |
| Tubulin β−2A chain | 3×Tg-AD | 3 | C↑ | Shen et al. 2015 | |
| Neuroinflammation | GFAP | SAMP8b | 12 | N↑ | Fiorini et al. 2013 |
| Protein Folding and Degradation | HSP90AB1 | 3×Tg-AD | 3 | C↑ | Shen et al. 2015 |
| Protein disulfide-isomerase A3 | 3×Tg-AD | 3 | C↑ | Shen et al. 2015 | |
| T-complex protein 1 subunit ε | 3×Tg-AD | 3 | C↑ | Shen et al. 2015 | |
| Signal Transduction | 14-3-3ζ/δ/γ | APP/PS1 KI | 1,9,12,15 | C↑ | Sultana et al. 2011a |
| 14-3-3ζ/δ | 3×Tg-AD | 3 | C↑ | Shen et al. 2015 | |
| Pin1 | J20 | 9 | N↓ | Robinson et al. 2011 | |
| APP/PS1 KI | 9,12,15 | C↑ | Sultana et al. 2011a |
Note: C, carbonylation; N, nitration;
oxidative modification was significantly increased;
oxidative modification was significantly decreased;
Antisense Oligonucleotide directed against Aβ region of APP gene;
Antisense Oligonucleotide directed against PS-1 gene;
The 3×Tg-AD mouse model develops age related progressive neuropathology including senile plaques, neurofibrillary tangles, and synaptic dysfunction (Oddo et al. 2003a). Increased intracellular Aβ is detected by 3 months of age with cognitive impairment observed at 4 months of age (Billings et al. 2005) and extracellular deposition occurs by 6 months of age (Oddo et al. 2003a,b). Redox proteomics analysis of carbonylated proteins in the hippocampus of 3 month-old 3×Tg-AD mice identified 14-3-3ζ/γ, mitochondrial aconitase, GS, GAPDH, α-enolase, phosphoglycerate kinase 1 (PGK1), heat shock protein 90-β, mitochondrial MDH, neurofilament light polypeptide, protein disulfide-isomerase A3, T-complex protein 1 subunit ε, and tubulin β−2A chain to be significantly oxidized compared to age-matched non-transgenic controls (Shen et al. 2015).
SAMP8 mice are a model for gerontological and age-related dementia research that exhibit learning and memory deficits with age (Flood and Morley 1993, 1998). These changes correlate with increased oxidative stress (Butterfield et al. 1997; Farr et al. 2003; Poon et al., 2005; Butterfield and Poon 2005) starting as early as 4 months. SAMP8 mice exhibit an age-related increase in APP (Morley et al. 2000; Nomura et al. 1996) and hippocampal Aβ peptide (Kumar et al. 2000; Takeda 2009) depositing as granules in the hippocampus by 6 months of age (Takemura et al. 1993; Del Valle et al. 2010;) with plaque formation late in life at 20 months (Morley et al. 2000). Cognitive deficits occur prior to plaque formation supporting the role for small, soluble oligomers of Aβ inducing oxidative damage resulting in learning and memory impairments. Consequently, the SAMP8 mouse is considered a model of oxidative stress and AD (Morley et al. 2012). Redox proteomics analysis of the brain of 12 month old SAMP8 mice identified lactate dehydrogenase 2 (LDH-2), creatine kinase (CK), DRP-2 (CRMP-2), and α-spectrin 2 to be significantly oxidized as indexed by protein carbonyls compared to 4 month old SAMP8 mice (Poon et al. 2004a). Antisense oligonucleotide (AO) directed against the Aβ region of APP gene in aged SAMP8 mice significantly decreased APP protein levels, reversed learning and memory deficits (Kumar et al. 2000) and significantly decreased brain Aβ levels and oxidative stress biomarkers compared to age-matched SAMP8 mice that received a random AO (Poon et al. 2004b). In this model, carbonylation of aldolase 3 (Aldo 3), coronin 1a (Coro 1a), and peroxiredoxin 2 (Prx2) was found to be significantly decreased in the 12-month-old SAMP8 mice that received the AO directed against the Aβ region of APP gene (Poon et al. 2005). Another study determined that the age-related increase in APP and Aβ may be due to an age-related increase in PS-1 protein level in the hippocampus of SAMP8 mice (Kumar et al. 2009). AO directed against the PS-1 gene in 12 month old SAMP8 mice resulted in significantly decreased PS-1 protein levels, oxidative stress parameters, and reversed learning and memory deficits in the hippocampus. In this model, nitration of LDH, DRP-1 (CRMP-1), dynamin-1 (Dyn-1), GFAP, vesicle-fusing ATPase (NSF), α-enolase, isocitrate dehydrogenase (IDH), actin-related protein 2 (Actr2), and septin-11 (SEP11) was significantly decreased in SAMP8 mice receiving AO directed against the PS-1 gene while nitration of DRP-2 (CRMP-2) and peptidase α (DPL2) was significantly increased (Fiorini et al. 2013).
The J20 mouse model expresses human APP with the Swedish (670/671KM->NL) and Indiana (717V->F) FAD mutations generating increased Aβ(1–42) by 2 months of age with plaques forming by 5 months of age (Mucke et al. 2000). This increase in soluble Aβ(1–42) correlates with a decrease in presynaptic terminals (Mucke et al. 2000) and an increase in oxidative stress (Butterfield et al. 2010) and learning and memory deficits (Mucke et al. 2000; Galvan et al. 2006; Harris et al. 2010) that again supports the role of soluble Aβ(1–42)-induced oxidative stress in synaptic toxicity in AD. Redox proteomics analysis has shown decreased nitration of phosphatidylethanolamine-binding protein 1 (PEBP-1) and Pin1 in brain of 9-month-old J20 mice compared to the age-matched non-transgenic control (Robinson et al. 2011).
Collectively, redox proteomics analyses of in vivo models of Aβ(1–42)-induced oxidative stress can be categorized as involved in cellular redox homeostasis and detoxification defense, glucose metabolism, synaptic plasticity, vesicle-mediated transport and cell structure, neuroinflammation, protein folding and degradation, and signal transduction and are consistent with reports of such functional proteins being oxidatively modified and usually dysfunctional in aMCI and AD brains (Sultana et al. 2006a,c, 2007; Reed et al. 2008; Aluise et al. 2011; Castegna et al. 2002a,b, 2003; Aksenov et al. 2001; Butterfield et al. 2006a).
In vivo Aβ(1–42)-induced protein oxidation: PCAD, MCI, AD, and DS Human Studies
Redox proteomics analyses were conducted to identify oxidatively modified proteins in brain representing all stages of the AD continuum and DS (Table 4). In PCAD inferior parietal lobule (IPL), a significant increase in insoluble monomeric Aβ(1–42) is observed compared to control, but no difference in oligomeric Aβ or oxidative stress biomarkers were detected (Aluise et al. 2010). MCI IPL, however, exhibits increased protein carbonyls compared to PCAD IPL. Redox proteomics analysis showed α-enolase and heat shock protein 90 (HSP90) to be significantly carbonylated in MCI IPL compared to PCAD IPL (Aluise et al. 2011). Carbonic anhydrase II (CA II), heat shock protein 70 (HSP70), mitogen-activated protein kinase I (MAPKI), and syntaxin binding protein I (SBP1) are also significantly carbonylated in MCI IPL compared to age-matched control (Sultana et al. 2010). In MCI hippocampus, α-enolase, GS, pyruvate kinase M2 (PKM2), and Pin1 were identified to be significantly carbonylated compared to age-matched control (Butterfield et al. 2006a). HNE-bound protein modifications have also been assessed in MCI hippocampus and IPL. In the hippocampus, α-enolase, LDH, PGK, HSP70, carbonyl reductase, and neuropolypeptide h3 (PEBP1) had significantly increased levels of protein-bound HNE while β-actin, PK, initiation factor α (eIF-α), and elongation factor Tu (EF-Tu) were identified in MCI IPL. ATP synthase was found to have increased levels of protein-bound HNE in both MCI hippocampus and IPL (Reed et al. 2008). Protein nitration in MCI IPL and hippocampus has also been assessed by redox proteomics. α-enolase was found to be significantly nitrated in both MCI IPL and hippocampus while glucose related protein precursor, aldolase, GST mu (GSTM3), multidrug resistant protein (MRP3), and 14-3-3γ were significantly nitrated in MCI IPL and peroxiredoxin 6 (Prx6), DRP-2 (CRMP-2), fascin 1, and HSP70 isoform A8 were significantly nitrated in MCI hippocampus (Sultana et al. 2007).
Table 4:
Oxidatively Modified Proteins Identified in aMCI, EAD, LAD, DS, and DS/AD Brain
| Protein | Disease State | Brain Region | Oxidative Modification | References |
|---|---|---|---|---|
| Cellular Redox Homeostasis and Detoxification Defense | ||||
| Carbonyl reductase | MCIa | HP | H | Reed et al. 2008 |
| Glutamate dehydrogenase (GDH) | DSa | FC | H | Di Domenico et al. 2014 |
| DS/ADa,b | FC | H | Di Domenico et al. 2014 | |
| Glutathione S-Transferase (GST) Mu | MCIa | IPL | N | Sultana et al. 2007 |
| Multidrug resistance protein 3 (MRP3) | MCIa | IPL | N | Sultana et al. 2007 |
| Peroxiredoxin 2 (Prx2) | DSa | FC | H | Di Domenico et al. 2014 |
| Peroxiredoxin 6 (Prx6) | MCIa | HP | N | Sultana et al. 2007 |
| LADa | HP | H | Perluigi et al. 2009 | |
| Cu,Zn Superoxide dismutase (SOD) | DS/ADa | FC | H | Di Domenico et al. 2014 |
| Mn Superoxide dismutase (SOD) | EADa | IPL | H | Reed et al. 2009 |
| LADa | IPL | H | Perluigi et al. 2009 | |
| Energy Metabolism | ||||
| Aconitase | LADa | HP | H | Perluigi et al. 2009 |
| DS/ADb | FC | H | Di Domenico et al. 2014 | |
| Aldolase | MCIa | IPL | N | Sultana et al. 2007 |
| EADa | IPL | C | Sultana et al. 2010 | |
| LADa | HP | H | Perluigi et al. 2009 | |
| DSa | FC | H | Di Domenico et al. 2014 | |
| ATP Synthase | MCIa | HP | H | Reed et al. 2008 |
| MCIa | IPL | H | Reed et al. 2008 | |
| EADa | IPL | H | Reed et al. 2009 | |
| LADa | HP | N | Sultana et al. 2006a | |
| LADa | IPL | H | Perluigi et al. 2009 | |
| Creatine Kinase BB (CK) | LADa | IPL | C | Castegna et al. 2002a |
| Cyt b-c1 RIeske Protein | DSa | FC | H | Di Domenico et al. 2014 |
| DS/ADa | FC | H | Di Domenico et al. 2014 | |
| α-enolase | MCIa | HP | C | Butterfield et al. 2006a |
| MCIa | HP | N | Sultana et al. 2007 | |
| MCIa | HP | H | Reed et al. 2008 | |
| MCIa | IPL | N | Sultana et al. 2007 | |
| MCIa | IPL | C | Aluise et al. 2011 | |
| EADa | IPL | H | Reed et al. 2009 | |
| LADa | HP | C | Sultana et al. 2006c | |
| LADa | HP | N | Sultana et al. 2006a | |
| LADa | HP | H | Perluigi et al. 2009 | |
| LADa | IPL | C | Categna et al. 2002b | |
| LADa | IPL | N | Categna et al. 2003 | |
| DS/ADa | FC | H | Di Domenico et al. 2014 | |
| Glucose Regulated Protein Precursor | MCIa | IPL | N | Sultana et al. 2007 |
| Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) | LADa | HP | N | Sultana et al. 2006a |
| DS/ADa | FC | H | Di Domenico et al. 2014 | |
| Lactate dehydrogenase (LDH) | MCIa | HP | H | Reed et al. 2008 |
| Malate dehydrogenase (MDH) | DS/ADa | FC | H | Di Domenico et al. 2014 |
| EADa | IPL | H | Reed et al. 2009 | |
| Phosphoglycerate kinase (PGK) | MCIa | HP | H | Reed et al. 2008 |
| Phosphoglycerate mutase 1 (PGM1) | EADa | IPL | C | Sultana et al. 2010 |
| LADa | HP | C | Sultana et al. 2006c | |
| Pyruvate kinase (PK) | MCIa | IPL | H | Reed et al. 2008 |
| DSa | FC | H | Di Domenico et al. 2014 | |
| MCIa | HP | C | Butterfield et al. 2006a | |
| Succinyl CoA-3-ketoacid-CoA transferase-1 (SCOT-1) | DSa | FC | C | Di Domentico et al. 2013 |
| Triose phosphate isomerase (TPI) | EADa | IPL | H | Reed et al. 2009 |
| LADa | HP | C | Sultana et al. 2006c | |
| LADa | IPL | N | Castegna et al. 2003 | |
| Excitotoxicity | ||||
| Glutamine Synthetase (GS) | MCIa | HP | C | Butterfield et al. 2006a |
| LADa | IPL | C | Castegna et al. 2002a | |
| LADa | IPL | H | Perluigi et al. 2009 | |
| Synaptic plasticity, vesicle-mediated transport and cell structure | ||||
| Carbonic anhydrase II (CA II) | MCIa | IPL | C | Sultana et al. 2010 |
| LADa | HP | C | Sultana et al. 2006c | |
| LADa | HP | N | Sultana et al. 2006a | |
| Dihydropyrimidinase-related protein 1 (DRP-1) | DS/ADa,b | FC | H | Di Domenico et al. 2014 |
| Dihydropyrimidinase-related protein 2 (DRP-2) | MCIa | HP | N | Sultana et al. 2007 |
| EADa | IPL | H | Reed et al. 2009 | |
| LADa | HP | C | Sultana et al. 2006c | |
| LADa | IPL | C | Castegna et al. 2002b | |
| LADa | IPL | H | Perluigi et al. 2009 | |
| DSa | FC | H | Di Domenico et al. 2014 | |
| DS/ADa,b | FC | H | Di Domenico et al. 2014 | |
| Fascin 1 | MCIa | HP | N | Sultana et al. 2007 |
| Neuropolypeptide h3 (PEBP1) | MCIa | HP | H | Reed et al. 2008 |
| LADa | IPL | N | Castegna et al. 2003 | |
| Syntaxin binding protein I (SBP1) | MCIa | IPL | C | Sultana et al. 2010 |
| DS/ADa,b | FC | H | Di Domenico et al. 2014 | |
| γ-synaptosomal protein like soluble N-ethylmaleimide-sensitive factor (γ-SNAP) | LADa | HP | C | Sultana et al. 2006c |
| Voltage-dependent anion-channel protein-1 (VDAC-1) | LADa | HP | N | Sultana et al. 2006a |
| β-actin | MCIa | IPL | H | Reed et al. 2008 |
| α-internexin | DSa | FC | H | Di Domenico et al. 2014 |
| Myelin binding protein (MBP) | DSa | FC | H | Di Domenico et al. 2014 |
| DS/ADb | FC | H | Di Domenico et al. 2014 | |
| Neurofilament medium polypeptide (NMP) | DS/ADa | FC | H | Di Domenico et al. 2014 |
| α-tubulin | LADa | HP | H | Perluigi et al. 2009 |
| Neuroinflammation | ||||
| Glial fibrillary acidic protein (GFAP) | EADa | IPL | C | Sultana et al. 2010 |
| DSa | FC | H | Di Domenico et al. 2014 | |
| DS/ADa | FC | H | Di Domenico et al. 2014 | |
| Protein Synthesis | ||||
| Elongation factor-Tu (EF-Tu) | MCIa | IPL | H | Reed et al. 2008 |
| Initiation factor α (eIF-α) | MCIa | IPL | H | Reed et al. 2008 |
| Protein Folding and Degradation | ||||
| Cathepsin D (CatD) | DSa | FC | C | Di Domentico et al. 2013 |
| 78kDa glucose-regulated protein (GRP78) | DSa | FC | C | Di Domentico et al. 2013 |
| DS/ADa,b | FC | H | Di Domenico et al. 2014 | |
| Heat shock cognate 71 (HSC71) | LADa | IPL | C | Castegna et al. 2002b |
| DS/ADa | FC | H | Di Domenico et al. 2014 | |
| Heat shock protein (HSP70) | MCIa | HP | H | Reed et al. 2008 |
| MCIa | HP | N | Sultana et al. 2007 | |
| MCIa | IPL | C | Sultana et al. 2010 | |
| Heat shock protein (HSP90) | MCIc | IPL | C | Aluise et al. 2011 |
| DS/ADb | FC | H | Di Domenico et al. 2014 | |
| T-complex protein 1 subunit β (TCPB) | DS/ADa | FC | H | Di Domenico et al. 2014 |
| Ubiquitin carboxy-terminal hydrolase L-1 (UCH-L1) | LADa | FC | C | Choi et al. 2004 |
| LADa | HP | C | Sultana et al. 2006c | |
| LADa | IPL | C | Castegna et al. 2002a | |
| DSa | FC | C | Di Domentico et al. 2013 | |
| DSa | FC | H | Di Domentico et al. 2014 | |
| Vo-ATPase | DSa | FC | C | Di Domentico et al. 2013 |
| Signal Transduction | ||||
| 14-3-3γ | MCIa | IPL | N | Sultana et al. 2007 |
| Mitogen-activated protein kinase I (MAPKI) | MCIa | IPL | C | Sultana et al. 2010 |
| Peptidylprolyl cis-trans isomerase-1 (Pin1) | MCIa | HP | C | Butterfield et al. 2006a |
| LADa | HP | C | Sultana et al. 2006b; Sultana et al. 2006c | |
Note: FC, frontal cortex; HP, hippocampus; IPL, inferior parietal lobule; C, carbonylation; N, nitration; H, HNE bound
compared to age-matched control
compared to DS brain
compared to PCAD
In EAD IPL, phosphoglycerate mutase 1 (PGM1), GFAP, and fructose bisphosphate aldolase C (FBA-C) are significantly carbonylated (Sultana et al. 2010), while MnSOD, α-enolase, ATP synthase, DRP-2 (CRMP-2), MDH, and triose phosphate isomerase (TPI) have significant increases in protein-bound HNE compared to age-matched control (Reed et al. 2009). Assessment of HNE-bound proteins in LAD have identified increased levels modifying MnSOD, ATP synthase, DRP-2 (CRMP-2), and GS in IPL and aldolase, aconitase, α-enolase, Prx6, and α-tubulin in hippocampus compared to respective age-matched controls (Perluigi et al. 2009). Also in LAD brain, ubiquitin carboxy-terminal hydrolase L-1 (UCH-L1), DRP-2 (CRMP-2) and α-enolase were found to be significantly carbonylated in both IPL and hippocampus compared to respective age-matched controls (Castegna et al. 2002a,b; Sultana et al. 2006c). Creatine kinase BB (CK BB), GS, and heat shock cognate 71 (HSC71) also were significantly carbonylated in IPL (Castegna et al. 2002a,b), and Pin1, PGM1, CA II, TP1, and γ-synaptosomal protein like soluble N-ethylmaleimide-sensitive factor (γ-SNAP) were significantly carbonylated in hippocampus (Sultana et al. 2006c). CAII, GAPDH, ATP synthase, and voltage-dependent anion-channel protein-1 (VDAC1) are significantly nitrated in LAD hippocampus, and TPI and neuropeptide h3 are increasingly nitrated in LAD IPL. α-enolase was found to be significantly nitrated in LAD IPL and hippocampus (Castegna et al. 2003; Sultana et al. 2006a). Frontal cortex of two FAD patients each with a mutation in PS1 have been analyzed using redox proteomics. Because of the limited sample size only proteins with elevated carbonylation compared to age-matched controls were reported. These proteins included γ-enolase, dimethylarginine dimethylaminohydrolase 1 (DMDMAH-1), UCH-L1, and actin (Butterfield et al. 2006b), consistent with the notion that glucose metabolism, nitric oxide metabolism, synaptic remodeling, and protein quality control are detrimentally affected in inherited AD.
As discussed previously, redox proteomics analyses of DS brain can provide insights into the in vivo effects of Aβ(1–42). In DS frontal cortex, GDH, Prx2, complex III Rieske protein (cyt b-c1), fructose bisphosphate aldolase-A, FBA-C, DRP-2, GFAP, UCH-L1, α-internexin, and myelin binding protein (MBP) have significantly elevated levels of protein-bound HNE (Di Domenico et al. 2014), while succinyl CoA-3-ketoacid-CoA transferase 1 (SCOT-1), cathepsin D (CatD), 78kDa glucose-regulated protein (GRP78), UCH L-1, and Vo-type proton ATPase (Vo-ATPase) were significantly carbonylated (Di Domenico et al. 2013) compared to age-matched control. Protein-bound HNE levels of Cu,ZnSOD, cyt b-c1, α-enolase, GAPDH, MDH, GFAP, HSC71, T-complex protein 1 subunit β (TCPB), and neurofilament medium polypeptide (NMP) were significantly increased in frontal cortex from DS with AD (DS/AD) compared to age-matched control while GDH, DRP-1, DRP-2, SBP1, GRP78, aconitase, HSP90B1 and MBP were significantly increased in DS/AD frontal cortex compared to DS (Di Domenico et al. 2014).
Redox proteomics analyses of MCI, AD, and DS brain provides insight into the proteins of the proteome that are particularly sensitive to oxidative modification. Notably, GS is oxidatively modified in MCI (Butterfield et al. 2006a) and LAD brain (Castegna et al. 2002a; Perluigi et al. 2009), and ATP synthase, α-enolase, and DRP-2 (CRMP-2) are oxidatively modified in MCI (Butterfield et al. 2006a; Sultana et al. 2007; Reed et al. 2008; Aluise et al. 2011), EAD (Reed et al. 2009) and LAD (Castegna et al. 2002b, 2003; Sultana et al. 2006a,c; Perluigi et al. 2009). α-enolase also was oxidatively modified in DS/AD brain, while DRP-2 was also oxidized in both DS and DS/AD brain (Di Domenico et al. 2014). Likewise, redox proteomics analyses provide a snapshot of the oxidative modification of the proteome at a given point in time. Interestingly, HSP 70 and HSP90 are only oxidized in MCI brain (Sultana et al. 2007, 2010; Reed et al. 2008; Aluise et al. 2011), suggesting that oxidative modification of these molecular chaperones and maintenance of proper protein folding may be affected early in the progression of AD. Similarly, PK which catalyzes the final step in aerobic glycolysis is oxidatively modified only in MCI (Butterfield et al. 2006a; Reed et al. 2008) and DS brain (Di Domenico et al. 2014). Aβ(1–42) induces oxidative modification of DRP-2 (Boyd-Kimball et al. 2005a) and PK (Sultana et al. 2006d) in vitro and GS in vivo (Boyd-Kimball et al. 2005c) strongly support the idea that Aβ(1–42) plays a significant role in the oxidative modification of these proteins in AD or DS brain.
Serum, CSF, and Peripheral Lymphocyte Mitochondria
Adaptation of redox proteomics methods to analyze plasma, serum, and cerebrospinal fluid (CSF) (Di Domenico et al. 2016a) and circulating biomarkers of protein oxidation in Alzheimer’s disease have been previously reviewed (Aluise et al. 2008; Di Domenico et al. 2011; Lista et al. 2013). In cerebrospinal fluid, decreased Aβ(1–42) and increased tau phosphorylated at threonine 181 (p-tau181) correlate with disease progression from MCI to AD (Mattsson et al. 2009; Di Domenico et al. 2016b). Just like changes in brain pathology, CSF levels of Aβ(1–42) and tau begin to change about two decades prior to the onset of symptoms, with changes in Aβ(1–42) preceding changes in tau (Wildsmith et al. 2014; Bateman et al. 2012; Buchhave et al. 2012). Redox proteomics analysis of CSF identified α−1β-glycoprotein, vitamin D-binding protein (DBP), ApoE, prostaglandin-H2 D-isomerase (PGDS), and α−1-anti-trypsin (A1AT) to be significantly carbonylated in both aMCI and AD compared to age-matched control. Gelsolin was the only protein identified to be significantly carbonylated in CSF of AD compared to aMCI (Di Domenico et al. 2016b). λ chain precursor has also been identified as significantly carbonylated in AD CSF compared to control (Korolainen et al. 2007). Redox proteomics analysis of plasma has identified A1AT, fibrinogen γ-chain precursor protein, transferrin, and hemopexin to be significantly carbonylated in AD compared to age-matched control (Choi et al. 2002; Yu et al. 2003). More recently, increased carbonylation of α2-macroglobulin has been identified in AD plasma compared to control, while increased carbonylation of haptoglobin has also been identified in AD plasma and aMCI plasma compared to control. Increased carbonylation of haptoglobin was also detected between AD and aMCI plasma (Cocciolo et al. 2012). Moreover, plasma levels of heme oxygenase −1/biliverdin reductase-A, that normally produce the antioxidant bilirubin, are found at different levels in plasma in AD (Di Domenico et al. 2012). More redox proteomics studies of serum and CSF are necessary to expand our understanding of the progression of AD and potentially identify additional biomarkers.
Peripheral lymphocyte mitochondria showed elevated oxidative stress in both aMCI and AD that correlated with decreased levels of small molecule antioxidants, with elevated levels of Aβ(1–42), and with decreased performance on tests of cognition (Sultana et al. 2011b, 2013b).
Redox Proteomics and Aβ(1–42)-mediated oxidative stress in the progression of AD
Aβ(1–42) induces oxidative stress by forming small soluble oligomers that insert into the lipid bilayer and initiate lipid peroxidation, forming free radicals that further propagate lipid peroxidation events by abstracting allylic hydrogen atoms from acyl chains of lipids in the lipid bilayer (Figure 1). This process leads to a chain reaction eventually resulting in lipid peroxidation products, such as HNE that further contribute to protein oxidation by reacting with proteins via Schiff base chemistry or with Cys, Lys, and His residues of proteins by Michael Addition (Butterfield et al. 2001, 2007, 2013; Butterfield and Lauderback 2002; Halliwell 2006; Di Domenico et al. 2017; Luczaj et al. 2017) (Figure 2). Such protein modifications result in conformational changes and often loss of function (Table 5) leading to necrotic or apoptotic cell death (Subramaniam et al. 1997; Butterfield and Stadtman 1997).
Figure 1:
Oligomeric Aβ(1–42)-induces lipid peroxidation. Oligomeric Aβ(1–42) embedded in the lipid bilayer initiates free radical formation (R.) mediated by Met 35 which leads to abstraction of a labile, allylic hydrogen atom from unsaturated fatty acids forming lipid radicals (L.) that rapidly combine with oxygen to form lipid peroxyl radicals (LOO.). Lipid peroxyl radicals propagate lipid peroxidation by abstracting allylic hydrogen atoms from other unsaturated fatty acids in the membrane forming lipid hydroperoxides (LOOH) and lipid radicals (L.), thereby propagating the chain reaction. The reactive lipid peroxidation product, 4-hydroxy-2-trans-nonenal (HNE) can be formed from lipid hydroperoxides of arachidonic acid, linoleic acid, and linolenic acid. This process of lipid peroxidation, coupled to HNE formation and subsequent reaction with and dysfunction of cellular proteins, amplifies greatly the effects of a small amount of free radical formation on Aβ(1–42).
Figure 2:
HNE is formed from arachidonic acid and leads to oxidative protein modifications by reacting with Cys, His, and Lys residues via Michael addition.
Table 5:
Summary of Oxidatively Modified Proteins Identified by Redox Proteomics and Enzymatic Activity in aMCI, AD, and DS Brain
| Protein | Disease State | Brain Region | Oxidative Modification | Enzyme Activity | References |
|---|---|---|---|---|---|
| Cellular Redox Homeostasis and Detoxification Defense | |||||
| Mn Superoxide dismutase (SOD) | EADa | IPL | H | ↓ | Reed et al. 2009 |
| Energy Metabolism | |||||
| Aconitase | LADa | HP | H | ↓ | Perluigi et al. 2009 |
| ATP Synthase | MCIa | HP | H | ↓ | Reed et al. 2008 |
| MCIa | IPL | H | ↓ | Reed et al. 2008 | |
| LADa | IPL | H | ↓ | Perluigi et al. 2009 | |
| α-enolase | MCIa | HP | C | ↓ | Butterfield et al. 2006a |
| EADa | IPL | H | ↓ | Reed et al. 2009 | |
| Lactate dehydrogenase (LDH) | MCIa | HP | H | ↓ | Reed et al. 2008 |
| Malate dehydrogenase (MDH) | EADa | IPL | H | ↑ | Reed et al. 2009 |
| Pyruvate kinase (PK) | MCIa | IPL | H | ↓ | Reed et al. 2008 |
| MCIa | HP | C | ↓ | Butterfield et al. 2006a | |
| Synaptic plasticity, vesicle-mediated transport and cell structure | |||||
| Carbonic anhydrase II (CA II) | LADa | HP | C | ↓ | Sultana et al. 2006c |
| Protein Folding and Degradation | |||||
| Ubiquitin carboxy-terminal hydrolase L-1 (UCH-L1) | LADa | HP | C | ↓ | Sultana et al. 2006c |
| DSa | FC | C | ↓ | Di Domenico et al. 2013 | |
| Signal Transduction | |||||
| Peptidylprolyl cis-trans isomerase-1 (Pin1) | MCIa | HP | C | ↓ | Butterfield et al. 2006a |
| LADa | HP | C | ↓ | Sultana et al. 2006b | |
Note: FC, frontal cortex; HP, hippocampus; IPL, inferior parietal lobule; C, carbonylation; N, nitration; H, HNE bound
compared to age-matched control
Imaging studies indicate that increase in brain Aβ(1–42) may begin up to 20 years prior to the onset of cognitive symptoms (Villemagne et al. 2013; Reiman et al. 2012; Jack et al. 2009; Bateman et al. 2012). Early detection of Aβ(1–42) pathology may allow a timeframe for interventions that may prevent or delay the onset of cognitive symptoms; however, a greater understanding of the brain chemistry changes resulting from the increase in Aβ(1–42) is necessary to elucidate the progression of AD. Redox proteomics is a high-throughput method that has provided insight into the proteins that are particularly susceptible to oxidative damage as AD neuropathology accumulates from PCAD through LAD (Swomley and Butterfield 2015; Sultana et al. 2013a; Sultana and Butterfield 2013; Reed et al. 2010; Butterfield and Sultana 2007). Here we will focus our discussion to proteins found to be oxidatively modified in two or more of the models previously described (Figure 3). These proteins that have been identified to be oxidatively modified can be broadly classified into the following categories: antioxidants and cellular detoxification defenses, energy yielding metabolism and mitochondrial dysfunction, excitotoxicity, synaptic plasticity and cell structure, neuroinflammation, protein folding and degradation, and signal transduction.
Figure 3:
Venn diagram of proteins commonly oxidized in vitro and in vivo by Aβ(1–42) and in human studies of aMCI, AD, and DS brain.
Abbreviations: CK creatine kinase, DRP-1 dihyropyrimidinase-related protein-1 or collapsin response mediated protein-1 (CRMP-1), DRP-2 dihyropyrimidinase-related protein-2 or collapsin response mediated protein-2 (CRMP-2), GAPDH glyceraldehyde-3-phosphate dehydrogenase, GFAP glial fibrillary acidic protein, GS glutamine synthase, GST glutathione S-transferase, HSP90 heat shock protein 90, MDH malate dehydrogenase, LDH lactate dehydrogenase, PEBP1 neuropolypeptide h3 or hippocampal cholinergic neurostimulating peptide precursor protein (HCNPpp), PGK phosphoglycerate kinase, PGM phosphoglycerate mutase, Pin1 peptidyl cis-trans isomerase-1, PK, pyruvate kinase, Prx2 peroxiredoxin 2.
Antioxidants and cellular detoxification defenses
GSTs catalyze the conjugation of HNE to the cysteinyl residue of glutathione (GSH) forming GS-HNE adducts to be cleared from the cell by the multidrug resistant protein, MRP-1 (Sharma et al. 2004; Balogh and Atkins 2011). GST is carbonylated in vivo in C. elegans expressing Aβ(1–42) (Boyd-Kimball et al. 2006) and in the canine model of aging (Opii et al. 2008). Additionally, GST is excessively nitrated in MCI IPL (Sultana et al. 2007) and has significantly elevated levels of protein-bound HNE in AD hippocampus resulting in significantly decreased activity (Sultana and Butterfield 2004; Lovell et al. 1998). Decreased GST activity significantly impacts the activity of this detoxification process preventing the clearance of HNE, allowing for increased accumulation of HNE (Singhal et al. 2015; Luczaj et al. 2017; Siems and Grune 2003) and the subsequent HNE-modification of other proteins.
Peroxiredoxins (Prxs) are a family of thiol-dependent peroxidases that rapidly reduce H2O2 (Wood et al. 2003). Prxs are subcategorized into 2-Cys-Prx or 1-Cys-Prx enzymes. 2-Cys-Prx isoforms function as dimers each containing a conserved Cys residue in the amino-terminal region that reacts with peroxides and is oxidized to sulfenic acid. The sulfenic acid moiety then oxidizes an additional conserved Cys residue in the carboxy-terminal region of the other subunit to form an intrasubunit disulfide bond that is resolved by thioredoxin in an NADPH-dependent reduction. 1-Cys-Prx isoforms react with peroxides in the same manner as 2-Cys-Prx, but function catalytically as a monomer and lack the sacrificial carboxy-terminal Cys residue (McBean et al. 2015). Oxidized 1-Cys-Prx isoforms form a disulfide linkage with GST that is resolved by successive reaction with GSH (Rhee and Kil 2017) (Figure 4). Prx2 is a 2-Cys-Prx that is expressed primarily in the cytosol of neurons (Hattori and Oikawa 2007) and is oxidized in DS brain (Di Domenico et al. 2014). Oxidation of Prx2 was significantly decreased in brain of SAMP8 mice treated with an antisense oligonucleotide (AO) directed against the Aβ region of APP indicating that oxidative modification of Prx2 is Aβ(1–42) dependent (Poon et al. 2005). Prx6 is a 1-Cys-Prx isoform that is expressed in the cytosol and nucleus of astrocytes and oligodendrocytes (Hattori and Oikawa 2007) and is oxidatively modified in MCI (Sultana et al. 2007) and LAD brain (Perluigi et al. 2009). Expression of Prx2 is increased in AD and DS brain (Kim et al. 2001; Krapfenbauer et al. 2003), but this may be a compensatory mechanism. Oxidative modification of Prx2 and Prx6 not only contribute to impairment of the antioxidant response in the central nervous system in AD, but also may impact the signaling properties of Prxs and their ability repair peroxidized cell membranes (Fisher 2017) and to prevent, or delay, apoptotic cell death (Hampton and O’Connor 2016). In addition to their antioxidant function, Prxs also exhibit thiol redox-regulated chaperone activity (Kumsta and Jakob 2009; Conway and Lee 2015). Irreversible oxidative modifications of Prxs including carbonylation, nitration, and protein-bound HNE may inhibit the thiol redox-regulated activation of Prx chaperone activity contributing to increased protein misfolding and aggregation in AD brain (Kundra et al. 2017).
Figure 4:
Mechanisms of reduction of H2O2 by 2-Cys-Prx and 1-Cys-Prx by peroxiredoxin are shown in A and B, respectively. The reader is referred to the text for further details.
Energy Yielding Metabolism and Mitochondrial Dysfunction
Glycolytic enzymes including aldolase, TPI, GAPDH, PGK, PGM, enolase, and PK are significantly oxidatively modified in AD brain (Sultana et al. 2006a,c, 2007, 2010; Perluigi et al. 2009; Reed et al. 2008, 2009; Castegna et al. 2003; Butterfield et al. 2006a). Of these, GAPDH was found to be oxidatively modified in primary neuronal culture treated with Aβ(1–42) (Boyd-Kimball et al. 2005b; Sultana et al. 2006d), in hippocampus of rats following ICV injection of Aβ(1–42) (Boyd-Kimball et al. 2006), in aged canine (Opii et al. 2008), in 3×Tg-AD mice (Shen et al. 2015), in LAD (Sultana et al. 2006a), and DS/AD brain (Di Domenico et al. 2014), while oxidation of PK was observed in MCI and DS and was induced by Aβ(1–42) in primary neuronal culture (Sultana et al. 2006d). α-enolase is extensively oxidized in multiple AD mouse models (Sultana et al. 2011a; Shen et al. 2015; Fiorini et al. 2013) and in MCI (Butterfield et al. 2006a; Sultana et al. 2007; Reed et al. 2008; Aluise et al. 2011), EAD (Reed et al. 2009), LAD (Castegna et al. 2002b, 2003; Sultana et al. 2006a,c; Perluigi et al. 2009), and DS/AD brain (Di Domenico et al. 2014). Decreased glucose catabolism in the progression of AD has been well documented with the use of PET imaging studies (Yamaguchi et al. 1997; Marcus et al. 1997; Kato et al. 2016). The brain preferentially utilizes glucose (Sokoloff et al. 1977), but can also utilize ketone bodies in times of need (Hertz and Rothman 2016), to meet its cellular energy needs; however, beyond the production of ATP, glucose is also needed as a precursor for neurotransmitter biosynthesis, and plays a role in regulation of cell death and autophagy (Hertz and Chen 2017; Mergenthaler et al. 2013). Oxidative modification of glycolytic enzymes could result in glucose hypometabolism in AD.
Mitochondrial dysfunction also plays a role in AD pathogenesis (Reddy and Reddy 2011; Tu et al. 2014). In an APP/PS1 transgenic mouse model of AD, greater mitochondrial dysfunction is evident in the hippocampus and cortex that corresponded with increased Aβ mitochondrial levels and cognitive deficits (Dragicevic et al. 2010). In female 3×Tg-AD mice, mitochondrial dysfunction corresponded with the onset of oxidative stress, but precedes the development of plaque and tangle neuropathology (Yao et al. 2009), suggesting the mitochondrial dysfunction is an early event in AD pathogenesis. MDH, an important enzyme in the tricarboxylic acid (TCA) cycle, has been identified by redox proteomics as oxidized by Aβ(1–42) in vitro (Sultana et al. 2006d) and in vivo (Boyd-Kimball et al. 2006) and in 3×Tg-AD mice (Shen et al. 2015), EAD (Reed et al. 2009), and DS/AD brain (Di Domenico et al. 2014). Beyond the TCA cycle, MDH is important in the malate-aspartate shuttle that regenerates cytosolic NAD+ for GAPDH and glycolytic activity. Aconitase, another TCA cycle enzyme, is oxidized in 3×Tg-AD mice (Shen et al. 2015) and in LAD (Perluigi et al. 2009) and DS/AD brain (Di Domenico et al. 2014). ATP synthase (complex V) is also oxidized in APP/PS1 double human mutant knock- in mice (Sultana et al. 2011a) and in MCI (Reed et al. 2008), EAD (Reed et al. 2009), and LAD brain (Sultana et al. 2006a; Perluigi et al. 2009). Oxidation and altered function of mitochondrial enzymes critical for maintaining cellular energy needs could contribute to synaptic dysfunction, neurite loss and cell death evident in AD brain (Figure 5). See further discussion of glucose dysmetabolism in the progression of AD below in the Conclusion and Future Directions section.
Figure 5:
A summary of the cytosolic and mitochondrial enzymes critical for energy yielding metabolism and mitochondrial function are shown. Enzymes that are oxidatively modified by HNE in the progression of AD are starred for emphasis. Note that a stoichiometry of two exists for all reactions shown following the production of GAP.
Abbreviations: G6P: Gluocose-6-Phosphate; PGI: Phosphoglucose isomerase; F6P: Fructose 6 Phosphate; PFK: Phosphofructokinase; F-1,6-BP: Fructose-1,6-Bisphosphatase; TPI: Triose Phosphate Isomerase; GAP: Glyceraldehyde-3-Phosphate; DHAP: Dihydroxyacetone Phosphate; GAPDH: Glyceraldehyde-3-Phosphate Dehydrogenase; 1,3-BPG: 1,3-Bisphosphoglycerate; PGK: Phosphoglycerate Kinase; 3PG: 3-Phosphoglycerate; PGM: Phosphoglycerate Mutase; 2PG: 2-Phosphoglycerate; PEP: Phosphoenolpyruvate; PK: Pyruvate Kinase; LDH: Lactate Dehydrogenase; PDH: Pyruvate Dehydrogenase; OAA: Oxaloacetate; IDH: Isocitrate Dehydrogenase; α-KG: α-Ketoglutarate; α-KGDH: α-Ketoglutarate Dehydrogenase; SDH: Succinate Dehydrogenase; MDH: Malate Dehydrogenase.
Excitotoxicity
Glutamate is an excitatory neurotransmitter that is cleared from the synapse by the glial glutamate transporter (GLT-1), also known as the excitatory amino acid transporter-2 (EAAT2), where it is converted to glutamine by glutamine synthetase (GS). GLT-1 activity is decreased in AD brain (Masliah et al. 1996), which is likely due to the elevated levels of HNE bound to GLT-1 in AD brain (Lauderback et al. 2001). Redox proteomics has identified GS as oxidatively modified in vivo in C. elegans expressing Aβ(1–42) (Boyd-Kimball et al. 2006), and in MCI (Sultana et al. 2010) and LAD brain (Castegna et al. 2002a; Perluigi et al. 2009). GS activity is significantly decreased in AD brain (Smith et al. 1991; Hensley et al. 1995) and is likely explained by the increased protein-bound HNE and carbonylation present in AD brain (Perluigi et al. 2009; Castegna et al. 2002a). Taken together, oxidation of GLT-1 and GS could result in decreased clearance of synaptic glutamate inducing excitotoxicity and neuronal death.
Synaptic plasticity and cell structure
Dihydropyrimidinase-related protein-2 (DRP-2), also known as collapsin response mediator protein-2 (CRMP-2), was first characterized as functioning in neurite outgrowth by guiding the axonal growth cone (Goshima et al. 1995; Inagaki et al. 2001). More recently, DRP-2 has been identified as a microtubule associated protein that functions as an adaptor in several additional processes including establishing neuronal polarity, kinesin-dependent transport, neurotransmitter release, and Ca2+ channel regulation (Hensley et al. 2011; Hensley and Kursula 2016). DRP-2 is oxidatively modified by Aβ(1–42) in vitro (Boyd-Kimball et al. 2005a) and in vivo in SAMP8 mice (Poon et al. 2004; Fiorini et al. 2013) and in MCI (Sultana et al. 2007), EAD (Reed et al. 2009), LAD (Categna et al. 2002b; Sultana et al. 2006c; Perluigi et al. 2009), DS, and DS/AD brain (Di Domenico et al. 2014). Cytoskeletal proteins β-actin and α-tubulin also are susceptible to oxidative modification by Aβ(1–42). β-Actin is oxidized in vitro and in vivo by Aβ(1–42)-related processes (Boyd-Kimball et al. 2005a, 2006), in APP/PS1 double human mutant knock-in mice (Sultana et al. 2011a), and in MCI and FAD brain (Reed et al. 2008; Butterfield et al. 2006b), while α-tubulin is oxidized in vivo by Aβ(1–42) (Boyd-Kimball et al. 2005c), in 3×Tg-AD (Shen et al. 2015), and in LAD brain (Perluigi et al. 2009). DRP-2 has been shown to mediate axonal growth by interacting with and stabilizing tubulin (Rogemond et al. 2008; Chae et al. 2009) and indirectly stabilizing actin microfilaments (Hensley and Kursula 2016). Oxidative modification and conformation changes of DRP-2, α-tubulin, and β-actin likely impacts this interaction in addition to vesicle-mediated transport and thereby contribute to the loss of cognition in AD.
The cholinergic system is significantly disrupted in AD brain (Ferreira-Vieira et al. 2016). Cholinergic neurons are lost in the progression of AD (Whitehouse et al. 1981; Whitehouse et al. 1982), and choline acetyl transferase (ChAT), which catalyzes the synthesis of acetylcholine (ACh), exhibits decreased activity in AD brain (Wilcock et al. 1982). Levels of HNE-bound ChAT are significantly increased by Aβ(1–42) in vitro (Butterfield and Lauderback 2002) suggesting that Aβ(1–42)-induced oxidative modification may contribute to the decreased ChAT activity observed in AD brain. Redox proteomics has identified neuropolypeptide h3 to be oxidatively modified in vivo in the J20 mouse (Robinson et al. 2011), and in MCI (Reed et al. 2008) and LAD brain (Castegna et al. 2003). Neuropolypeptide h3 is also known as phosphatidylethanolamine binding protein-1 (PEBP-1), which is a pleiotropic protein that binds ATP in addition to phosphatidylethanolamine (Sato et al. 2017). PEBP-1 is also known as hippocampal cholinergic neurostimulating peptide precursor protein (HCNPpp) and Raf kinase inhibitor protein (RKIP). Reduced HCNPpp gene expression has been shown in AD hippocampus (Maki et al. 2002) and HCNPpp has been shown to co-localize with DRP-2 at presynaptic terminals in hippocampal neurons (Kato et al. 2012). HCNP, an 11 amino acid peptide, is cleaved from within the amino-terminus of HCNPpp and increases ACh synthesis by increasing ChAT levels (Ojika et al. 2000). Oxidative modification of HCNPpp may further disrupt presynaptic function in AD brain by impacting its interaction with DRP-2 and may potentially alter its recognition and cleavage to yield HCNP further impacting cholinergic neurotransmission.
Neuroinflammation
GFAP is the main constituent of the intermediate filament system in adult astrocytes and is considered a marker of reactive gliosis (Pekny and Pekna 2004). Reactive astrocytes can provide some neuroprotective and repair functions in mild to moderate astrogliosis; however, extreme astrogliosis can result in glial scar formation that is reported to inhibit axon regeneration (Sofroniew 2009; Silver and Miller 2004). Reactive astrogliosis is evident in MCI, suggesting it occurs early in the progression of AD (Carter et al. 2012). Reactive astrocytes are co-localized with senile plaques (Nagele et al. 2003) and produce proinflammatory signals (Li et al. 2011) that enhance Aβ(1–42) production in astrocytes (Blasko et al. 2000; Frost and Li 2017) and impair microglial phagocytosis (Koenigsknecht-Talboo and Landreth 2005). Aβ(1–42) has been shown to play a role in initiating inflammation in the CNS (Minter et al. 2016). GFAP is oxidized in vitro (Boyd-Kimball et al. 2005a) by Aβ(1–42), and in vivo in SAMP8 mice brain (Fiorini et al. 2013) and EAD (Sultana et al. 2010), DS, and DS/AD brain (Di Domenico et al. 2014). Oxidation of GFAP could indicate damage to astrocytes consistent with astrocytic dysfunction (Acosta et al. 2017; Garwood et al. 2017) and neuroinflammation (Latta et al. 2015) evidenced in AD brain and exacerbate glutamate excitotoxicity as previously described.
Protein folding and degradation
Protein homeostasis, or proteostasis, is the maintenance of the proteome such that all proteins are in the correct conformation, location, and concentration for their function. Structure dictates function; consequently, chaperones are required to prevent misfolding while sorting and trafficking functions are required to target proteins to the appropriate cellular location, and, in addition, the concentration of each protein is controlled by regulating protein synthesis and degradation (Klaips et al. 2018). The Unfolded Protein Response (UPR) is a protective mechanism in which the endoplasmic reticulum (ER) responds to increased levels of unfolded or misfolded proteins in the ER lumen. UPR works in concert with endoplasmic reticulum associated degradation (ERAD) that directs unfolded proteins for destruction by the ubiquitin proteasome system (UPS) (Penke et al. 2018). Failure of the UPR to keep up this screening mechanism leads to the buildup of misfolded proteins in the ER which accumulate in mitochondria-associated ER membranes and cause mitochondrial dysfunction (Volgyi et al. 2015; Schon and Area-Gomez 2013) resulting in aberrant APP processing, decreased energy production, and triggering apoptotic cell death consistent with AD (Area-Gomez and Schon 2016; Hiramatsu et al. 2015; Safra et al. 2013). Several molecular chaperones have been identified by redox proteomics to be oxidatively modified AD brain and models thereof. HSP60 is increasingly carbonylated by Aβ(1–42) in vivo (Boyd-Kimball et al. 2006), while HSC71 exhibited increased carbonylation in LAD brain (Castegna et al. 2002b) and increased protein-bound HNE in DS/AD brain (Di Domenico et al. 2014). HSP70 is oxidized and nitrated in MCI brain (Reed et al. 2008; Sultana et al. 2007, 2010), and HSP90 is oxidatively modified in 3×Tg-AD mice (Shen et al.2015) and in MCI (Aluise et al. 2011) and DS/AD brain (Di Domenico et al. 2014). Oxidation of HSPs may prevent appropriate interactions with target proteins, resulting in increased protein misfolding and impaired repair mechanisms consistent with the increased protein aggregation evident in AD brain (Ashraf et al. 2014; Ross and Poirier 2004). Additionally, molecular chaperones including HSC71, HSP70, and HSP90 have been found in the synaptic compartment and play an important role in maintaining synaptic proteostasis (Gorenberg and Chandra 2017). Oxidation and altered function of these chaperones could further contribute to loss of synaptic plasticity and decreased cognition.
Proteasomal activity is decreased in AD brain (Keller et al. 2000) with a reduction in trypsin and chymotrypsin-like activities being reported (Lopez-Salon et al. 2003; Mishto et al. 2006). A similar decrease in proteasomal activity also exists in DS brain (Di Domenico et al. 2013). Inhibition of proteasomal activity impairs synaptic plasticity in animals (Lopez-Salon et al. 2001; Fonseca et al. 2006), which may indicate that decreased proteasomal activity in AD brain may play a role in loss of synaptic plasticity. Oligomeric Aβ(1–42) inhibits proteasomal activity in vitro, and proteasomal function decreases in 3×Tg-AD mice at ages consistent with oligomeric Aβ(1–42) production suggesting that Aβ(1–42) may also inhibit proteasomal function in vivo (Tseng et al. 2008). Redox proteomics analysis of C. elegans expressing Aβ(1–42) identified both α- and β-proteasomal subunits to be oxidatively modified (Boyd-Kimball et al. 2006) suggesting a likely mechanism by which proteasome function is decreased in AD brain.
Aβ(1–42) induces inhibition of long-term potentiation (LTP), a form of synaptic plasticity associated with learning and memory, in hippocampal slices from wild type mice (Cullen et al. 1997; Walsh et al. 2002) and an APP/PS1 transgenic mouse model that overexpresses Aβ(1–42) also shows loss of LTP as early as 3 months of age (Trinchese et al. 2004). UCH-L1 ameliorates Aβ(1–42)-induced LTP loss in vitro and in vivo. This APP/PS1 transgenic mouse model of AD also shows no difference in the protein level of UCH-L1 in the hippocampus, but rather a shift in UCH-L1 from soluble to insoluble with a significant decrease in UCH-L1 specific activity in the insoluble fraction compared to the soluble fraction (Gong et al. 2006). UCH-L1 is an abundant protein localized to neurons that is a deubiquitinating enzyme (Wilkinson et al. 1989; Nijman et al. 2005), but also has been reported to stabilize monoubiquitinylated proteins in vivo (Osaka et al. 2003) and is itself regulated by ubiquitinylation (Setsuie and Wada 2007; Bishop et al. 2016). In dimeric form, UCH-L1 has ATP-independent ligase activity (Liu et al. 2002). Redox proteomics identified that brain-resident UCH-L1 is oxidatively modified in FAD (Butterfield et al. 2006b), LAD (Castegna et al. 2002a; Choi et al. 2004; Sultana et al. 2006c), and DS (Di Domenico et al. 2013, 2014). Additionally, UCH-L1 activity is significantly decreased in AD brain compared to age-matched control, suggesting that the increased carbonylation of the protein impairs its function (Sultana et al. 2006c). Likewise, oxidative modification of UCH-L1 by HNE significantly decreases its hydrolase activity (Nishikawa et al. 2003) while significantly increasing its insolubility and protein aggregation, likely due to structural alterations (Kabuta et al. 2008). Taken together, these studies suggest that oxidative modification of UCH-L1 causes conformational change resulting in loss of deubiquitinylation activity, resulting in increased protein aggregation and impaired UPS function and loss of synaptic plasticity consistent with what is known in AD.
Signal transduction
14-3-3 proteins are highly expressed in neuronal cytosol but are also detected in other cellular compartments. 14-3-3 proteins consist of 7 isoforms that have been found to interact with up to 200 different proteins to regulate metabolism, cell cycle, differentiation, autophagy, and apoptosis (Umahara et al. 2012; Steinacker et al. 2011; Heverin et al. 2012). 14-3-3 proteins function by inducing conformational change in a target, by using their hydrophobic domain to occlude structural features of a target, or by scaffolding (Heverin et al. 2012). Decreased expression of 14-3-3ζ induces an ER stress response and exacerbates excitotoxicity in vitro (Murphy et al. 2008) and overexpression of 14-3-3ζ ameliorates these alterations in vivo (Brennan et al. 2013). 14-3-3ζ also is reported to regulate neurite outgrowth (Ramser et al. 2010), differentially regulate protein kinase C (Acs et al. 1995) and may act to sequester misfolded proteins (Kaneko and Hachiya 2006). 14-3-3 proteins co-localize with neurofibrillary tangles (NFTs) in AD brain (Layfield et al. 1996) and 14-3-3ζ co-immunoprecipitates with microtubule associated tau (Hashiguchi et al. 2000). 14-3-3ζ facilitates glycogen synthase kinase 3β (GSK3β)-dependent phosphorylation of tau in culture (Agarwal-Mawal et al. 2003; Yuan et al. 2003) suggesting a role for 14-3-3ζ in formation of neurofibrillary tangles (Sluchanko and Gusev 2011; Li and Paudel 2016). 14-3-3ζ was identified to be oxidatively modified by Aβ(1–42) in vitro (Boyd-Kimball et al. 2005b; Sultana et al. 2006) and in vivo (Boyd-Kimball et al. 2005c) and in APP/PS1 double human mutant knock-in (Sultana et al. 2011a) and 3×Tg-AD mice (Shen et al. 2015). It should be noted that oxidized 14-3-3ζ was detected at an early age in both transgenic mouse models. Thus, oxidative modification of 14-3-3ζ occurred prior to Aβ deposition in the APP/PS1 double human mutant knock-in mice and prior to both Aβ deposition and tau pathology in the 3×Tg-AD mice. 14-3-3γ protein levels are increased in AD brain (Fountoulakis et al. 1999) and 14-3-3γ is oxidatively modified in MCI brain (Sultana et al. 2007) indicating that oxidative modification of 14-3-3 occurs early in the pathogenesis of AD and could have impacts on axonal guidance and transport, protein aggregation, autophagy, and apoptosis, all functions affected in AD.
Pin1 is a peptidyl prolyl cis/trans isomerase that induces a conformational change in phosphoproteins possessing phosphorylated Ser/Thr-Pro motifs (Lu et al. 1996; Lu et al. 1999a; Zhou et al. 1999; Liou et al. 2011). Notably, Pin1 activity is decreased by phosphorylation post-translational modification (Lu and Zhou 2007). In the CNS, Pin1 is expressed primarily in neurons and is mainly localized to the nuclei in normal brain; however, in AD brain, the Pin1 is colocalized in the cytoplasm with neurofibrillary tangles and purifies with paired helical filaments of hyperphosphorylated tau from AD brain (Lu et al. 1999b; Ramakrishnan et al. 2003). p-Thr231 tau has been shown to promote further phosphorylation of tau (Lin et al. 2007) leading to hyperphosphorylation (Hamdane et al. 2003). p-Thr231 tau is a target for Pin1 binding, and conformational change of the peptidyl proline bond in tau from cis to trans facilitates phosphoprotein phosphatase A2 (PPA2) mediated dephosphorylation of tau (Lu et al. 1999b; Ranganathan et al. 1997; Zhou et al. 2000). Pin1 knockout mice develop tau hyperphosphorylation and filament formation with age (Liou et al. 2003) and, when Pin1 knockout mice were crossed with Tg2576 mice that overexpress APP with the Swedish mutations K670N and M671L, knockout of Pin1 was found to increase amyloidogenic processing of APP resulting in increased intracellular Aβ(1–42) accumulation (Pastorino et al. 2006). Redox proteomics has identified Pin1 to be oxidatively modified in J20 (Robinson et al. 2011) and APP/PS1 double human mutant knock-in mice (Sultana et al. 2011a) and in MCI (Butterfield et al. 2006a) and LAD brain (Sultana et al. 2006b,c). Pin1 activity is significantly deceased in both MCI (Butterfield et al. 2006a) and LAD brain (Sultana et al. 2006b). Further study has shown that Cys113 of Pin1 is oxidatively modified in vivo in AD brain and in AD mouse models. In vitro oxidation of Cys113 results in loss of function, but not substrate recognition indicating that oxidized Pin1 can bind and trap substrates but be unable to complete the catalytic cycle. Mutation of this residue to alanine resulted in loss of catalytic function confirming that Cys113 is critical for Pin1 activity (Chen et al. 2015). Taken together, as Pin1 activity is proposed to promote nonamyloidogenic processing of APP, decreased Pin1 activity could shift APP processing further toward the amyloidogenic pathway resulting in increased production of Aβ(1–42) (Pastorino et al. 2006). Likewise, as Pin1 plays a role in regulating the phosphorylation state of tau, impaired Pin1 activity could lead to tau hyperphosphorylation and neurofibrillary tangles present in AD brain (Wang et al. 2007; Zhou et al. 2000). Impaired Pin1 activity in AD brain could also affect cell cycle regulation (Lin et al. 2015), UPS protein degradation (Liou et al. 2011) and synaptic plasticity (Xu et al. 2017).
Conclusion and Future Directions
Redox proteomics has been invaluable in identifying proteins that are particularly sensitive to oxidative modification pinpointing molecular targets in cellular processes or signaling pathways that are damaged and may be dysfunctional. In PCAD brain total Aβ(1–42) is significantly increased, but no significant difference in oxidative stress biomarkers were detected compared to control brain (Aluise et al. 2010); However, in MCI only small differences in AD neuropathology are observed compared to PCAD, but protein carbonyls are significantly increased in MCI brain compared to PCAD brain (Aluise et al. 2011). Some protein expression changes exist in PCAD brain compared to control brain (Aluise et al. 2010), but in our hands no oxidatively modified proteins were detected until MCI (Aluise et al. 2011) providing further evidence that a window of opportunity for treatment or lifestyle interventions may exist if AD can be detected in its earliest stages. Redox proteomics has the potential to screen for oxidized proteins in peripheral tissues; however, more studies of peripheral tissues along the progression of PCAD to LAD are needed to identify possible peripheral biomarkers that correlate with the changes observed in brain. Such studies have the potential to lead to the development of tools that could aid in diagnosis and staging the of disease beyond our current methods.
Overproduction and accumulation of Aβ(1–42) is known to induce oxidative stress and is key to the neuropathogenesis of AD. Redox proteomics has provided insight into the molecular targets susceptible to Aβ(1–42)-induced oxidative modification. In this review, we surveyed the proteins identified by redox proteomics to be oxidized by Aβ(1–42) in vitro and in vivo and discussed these in the context of oxidatively modified proteins identified by redox proteomics analyses of animal models of AD, human FAD, PCAD, MCI, EAD, LAD, DS and DS/AD brain. These commonalities indicate that Aβ(1–42)-induced oxidative modifications involve proteins that largely contribute to decreased energy yielding metabolism, synaptic dysfunction and excitotoxicity, and loss of proteostasis due to impaired molecular chaperones and degradation contributing to protein misfolding and aggregation, altered APP processing yielding increased production of Aβ(1–42) and, ultimately, resulting in cell death (Figure 6). Taken together, these redox proteomics studies indicate that Aβ(1–42)-mediated oxidative stress occurs early in AD progression. Consequently, improved access to biomarker imaging and the identification of treatments to reduce Aβ production or the oxidative damage induced by Aβ could be beneficial in preventing or delaying the progression of AD.
Figure 6:
Aβ(1–42)-mediated cell death is initiated by lipid peroxidation. Oligomeric Aβ(1–42)-embeds in the lipid bilayer inducing lipid peroxidation and propagating free radical reactions that oxidatively modify proteins resulting in conformational change and altered function impairing glucose metabolism, synaptic plasticity, synaptic glutamate clearance, and proteostasis, ultimately leading to cell death.
Indeed, a recent study demonstrates the value of imaging modalities in determining the order of pathological alterations in the progression of AD (Gordon et al. 2018). Consistent with our findings using redox proteomics and our overall Aβ(1–42)-centered hypothesis for oxidative stress, glucose dysmetabolism, and neuronal death in AD (Butterfield 2014; Butterfield and Boyd-Kimball 2018; Butterfield and Lauderback 2002; Butterfield et al. 2001, 2002, 2007, 2013), Gordon et al. (2018) demonstrated using PET imaging on thousands of individuals who are known to have dominantly inherited AD over a period of 22 years prior to expected onset of symptoms to 3 years following symptoms (the DIAN Network) that Aβ(1–42) deposition was the first pathological alteration observed, followed later by glucose dysmetabolism. In the current review, Aβ(1–42) oligomers were shown to oxidatively modify glycolytic and TCA enzymes and portions of ATP synthase, thereby decreasing glucose metabolism resulting in lower levels of ATP. This, in turn, leads to loss of neuronal membrane potential, opening voltage-gated Ca2+ channels with consequent influx of detrimental Ca2+, and eventual neuronal death. Gordon et al. (2018) showed by MRI that the third temperol alteration in AD pathology was thinning of the hippocampus and frontal cortex, consistent with neuronal death, in agreement with our redox proteomics findings and overall hypothesis.
Redox proteomics has identified potential promising therapeutic targets and pathways for eventually slowing if not halting progression of this devastating dementing disorder that is AD. Continued use of redox proteomics in the stages of AD likely will provide additional insights and new targets and pathways that may be beneficial in treating this disease.
ACKNOWLEDGEMENTS
This work was supported in part by grants from the National Institute on Aging. We thank the faculty of the Sanders-Brown Center on Aging for providing well-characterized specimens for the studies from our laboratory mentioned in this review.
Abbreviations:
- 3-NT
3-nitrotyrosine
- 3×Tg-AD
triple transgenic AD mouse
- A1AT
α−1-anti-trypsin
- Actr2
actin-related protein 2
- Acyl CoA DH
acyl-CoA dehydrogenase
- ADK
adenosine kinase
- AK
arginine kinase
- Aldo 3
aldolase 3
- aMCI
Amnestic Mild Cognitive Impairment
- AO
antisense oligonucleotide
- ApoE
Apolipoprotein E
- APP
Amyloid Precursor Protein
- Aβ
Amyloid beta-peptide
- CA II
carbonic anhydrase II
- CatD
cathepsin D
- ChAT
choline acetyltransferase
- CK BB
creatine kinase BB
- CK
creatine kinase
- Coro 1a
coronin 1a
- CRMP-1
collapsing response mediated protein-1
- CRMP-2
collapsing response mediated protein-2
- cyt b-c1
complex III Rieske protein
- DBP
vitamin D-binding protein
- DMDMAH-1
dimethylarginine dimethylaminohydrolase 1
- DPL2
peptidase α
- DRP-1
dihydropyrimidinase-related protein-1
- DRP-2
dihydropyrimidinase-related protein-2
- DS
Down syndrome
- DS/AD
Down syndrome with Alzheimer’s disease
- Dyn-1
dynamin-1
- EAAT2
excitatory amino acid transporter-2
- EAD
Early Alzheimer’s disease
- EF-1γ
elongation factor 1 γ
- EF-Tu
elongation factor Tu
- eIF-α
initiation factor α
- ERAD
endoplasmic reticulum associated degradation
- FAD
Familial Alzheimer’s disease
- FBA-C
fructose bisphosphate aldolase C
- GAPDH
glyceraldehyde-3-phosphate dehydrogenase
- GDH
glutamate dehydrogenase
- GFAP
glial fibrillary acid protein
- GLT-1
glial glutamate transporter
- GRP78
78kDa glucose-regulated protein
- GS
glutamine synthetase
- GSH
glutathione
- GST
glutathione-S-transferase
- GSTM3
GST mu
- HCNP
hippocampal cholinergic neurostimulating peptide
- HCNPpp
hippocampal cholinergic neurostimulating peptide precursor protein
- HNE
4-hydroxy-2-trans-nonenal
- HSC71
heat shock cognate 71
- HSP60
chaperonin 60
- HSP70
heat shock protein 70
- HSP90
heat shock protein 90
- ICV
intracerebral ventricular
- IPL
inferior parietal lobule
- LAD
Late Alzheimer’s disease
- LBP
lipid binding protein
- LDH-2
lactate dehydrogenase 2
- MAPKI
mitogen-activated protein kinase I
- MBP
myelin binding protein
- MCI
Mild Cognitive Impairment
- MDH
malate dehydrogenase
- MnSOD or SOD2
manganese superoxide dismutase
- MRLC
myosin regulatory light chain
- MRP1
multidrug resistant protein 1
- MRP
multidrug resistant protein
- NBM
nucleus basalis magnocellularis
- NMP
neurofilament medium polypeptide
- NSF
vesicle-fusing ATPase
- PCAD
Preclinical Alzheimer’s disease
- PDH
pyruvate dehydrogenase
- PEBP-1
phosphatidylethanolamine-binding protein 1 or neuropolypeptide h3
- PET
Positron Emission Tomography
- PGDS
prostaglandin-H2 D-isomerase
- PGK1
phosphoglycerate kinase 1
- PGM1
phosphoglycerate mutase 1
- Pin1
peptidylprolyl cis-trans isomerase-1
- PK
pyruvate kinase
- PKM2
pyruvate kinase M2
- Prx2
peroxiredoxin 2
- Prx6
peroxiredoxin 6
- Prxs
peroxiredoxins
- PS-1
presenilin 1
- SAMP8
senescence accelerated mouse
- SBP1
syntaxin binding protein I
- SCOT-1
succinyl CoA-3-ketoacid-CoA transferase 1
- SEP11
septin-11
- TCA
tricarboxylic acid cycle
- TCPB
T-complex protein 1 subunit β
- TK
transketolase
- UCH-L1
ubiquitin carboxy-terminal hydrolase L-1
- UPR
Unfolded Protein Response
- UPS
ubiquitin proteasome system
- VDAC1
voltage-dependent anion-channel protein-1
- Vo-ATPase
Vo-type proton ATPase
- γ-SNAP
soluble N-ethylmaleimide-sensitive factor
Footnotes
CONFLICT OF INTEREST STATEMENT
The authors have no conflicts of interest to declare.
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