Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: Insights into the development of Alzheimer's disease

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Abstract

Mild cognitive impairment (MCI) is generally referred to the transitional zone between normal cognitive function and early dementia or clinically probable Alzheimer's disease (AD). Oxidative stress plays a significant role in AD and is increased in the superior/middle temporal gyri of MCI subjects. Because AD involves hippocampal-resident memory dysfunction, we determined protein oxidation and identified the oxidized proteins in the hippocampi of MCI subjects. We found that protein oxidation is significantly increased in the hippocampi of MCI subjects when compared to age- and sex-matched controls. By using redox proteomics, we determined the oxidatively modified proteins in MCI hippocampus to be α-enolase (ENO1), glutamine synthetase (GLUL), pyruvate kinase M2 (PKM2) and peptidyl-prolyl cis/trans isomerase 1 (PIN1). The interacteome of these proteins revealed that these proteins functionally interact with SRC, hypoxia-inducible factor 1, plasminogen (PLG), MYC, tissue plasminogen activator (PLAT) and BCL2L1. Moreover, the interacteome indicates the functional involvement of energy metabolism, synaptic plasticity and mitogenesis/proliferation. Therefore, oxidative inactivation of ENO1, GLUL and PIN1 may alter these cellular processes and lead to the development of AD from MCI. We conclude that protein oxidation plays a significant role in the development of AD from MCI and that the oxidative inactivation of ENO1, GLUL, PKM2 and PIN1 is involved in the progression of AD from MCI. The current study provides a framework for future studies on the development of AD from MCI relevant to oxidative stress.

Introduction

Mild cognitive impairment (MCI) is generally referred to the transitional zone between normal cognitive aging and early dementia or clinically probable Alzheimer's disease (AD) (Winblad et al., 2004). Most individuals with MCI eventually develop AD, which suggests that MCI may be the earliest phase of the AD (Almkvist et al., 1998, Flicker et al., 1991, Luis et al., 2003, Morris et al., 2001). Although a variety of criteria are used to define MCI, they have in common that (a) MCI is referred to as the measurable cognitive deficits of non-demented persons and (b) MCI represents a clinical syndrome that does not fulfil a diagnosis of dementia but leads to a high risk of progressing to a dementia disorder (Winblad et al., 2004). When persons are diagnosed with MCI, most progress to AD and other dementia types, but some are stable or even recover (Winblad et al., 2004). Moreover, neuroimaging studies by magnetic resonance imaging (MRI) demonstrate the atrophy of the hippocampus or entorhinal cortex in MCI patients, indicating the relationships with transition of normal aging to MCI then later to clinical AD (de Leon et al., 2004).

Oxidative stress plays a significant role in AD (Butterfield et al., 2001, Butterfield and Lauderback, 2002, Giasson et al., 2002, Markesbery, 1997, Zhu et al., 2004). Manifested by elevated levels of nucleic acid oxidation, protein oxidation and lipid peroxidation, oxidative damage is most severe in AD hippocampus, a brain region that is responsible for memory processing and cognitive function (Butterfield et al., 2001, Butterfield and Lauderback, 2002). Although the role oxidative stress plays in AD is now well recognized, it remains unclear whether oxidative stress is a primary event or an epiphenomenon of AD progression. The highest level of oxidative damage is correlated to the brain regions that exhibit high levels of amyloid β-peptide (Aβ) and the most neuronal denegation in AD (Butterfield et al., 2001, Butterfield and Kanski, 2001, Butterfield and Lauderback, 2002, Giasson et al., 2002, Hensley et al., 1995a, Markesbery, 1997, Markesbery and Carney, 1999, Zhu et al., 2004). Moreover, oxidative stress-mediating entities per se induce neuronal death in vitro; and protein oxidation and lipid peroxidation in the superior and middle temporal gyri (SMTG) of MCI patients are increased (Keller et al., 2005). All of these studies strongly suggest that oxidative stress is indeed a primary event in the development of AD. To gain insight into the primary role of oxidative stress in the development of MCI to AD, we used redox proteomics to identify the proteins that are oxidatively modified in the hippocampus of MCI. We found that α-enolase (ENO1), glutamine synthetase (GLUL), pyruvate kinase M2 (PKM2) and peptidyl-prolyl cis/trans isomerase 1 (PIN1) are significantly oxidized in the hippocampi of MCI subjects when compared to that in control.

Section snippets

Subjects

The normal control subjects in this study were four females and two males, and the average age was 82 ± 2.6 years. The amnestic MCI patients were four females and two males, and the average age was 88 ± 1.5 years (Table 1). All subjects came from our longitudinally followed normal control group that has annual neuropsychological testing and neurological and physical examinations every 2 years. Control subjects had: (a) no cognitive complaints; (b) normal cognitive test scores, especially

Results

To determine if protein oxidation occurs in MCI subjects, the total protein carbonyl level of hippocampi of MCI patients was compared to control subjects. The average age and postmortem interval (PMI) of the control and MCI subjects were not statistically different (Table 1). However, the mean brain weight of MCI subjects was significantly lower (10%) than that of the controls (Table 1). Moreover, the Braak stage of control subjects ranged between I and II, whereas the MCI subjects ranged

Discussion

Because hippocampal dysfunction is involved early in AD (Barnes, 1988) and since MCI precedes AD (Petersen, 2003, Winblad et al., 2004), investigation of oxidative stress in hippocampi of MCI subjects can determine if oxidative stress is a primary event or an epiphenomenon in the development of AD. The current study demonstrates that protein oxidation is significantly increased in the hippocampi of MCI subjects when compared to age- and sex-matched controls (Table 1), which suggests that

Acknowledgments

This work was supported in part by grants from the National Institutes of Health AG-10836 (D.A.B.); AG-05119 (W.R.M., D.A.B.); and AG-05144 (W.R.M.). The authors also wish to thank Drs. Fred Schmitt, Richard Kryscio, Charles Smith, Greg Cooper and David Wekstein for clinical data, diagnosis information and tissue procurements. Thanks also to Ms. Paula Thomason for editorial assistance.

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