Proteomic identification of nitrated brain proteins in early Alzheimer's disease inferior parietal lobule

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in multiple cognitive domains. Its pathological hallmarks include senile plaques and neurofibrillary tangles. Mild cognitive impairment (MCI) is the earliest detectable stage of AD with limited symptomology and no dementia. The yearly conversion rate of patients from MCI to AD is 10-15%, although conversion back to normal is possible in a small percentage. Early diagnosis of AD is important in an attempt to intervene or slow the advancement of the disease. Early AD (EAD) is a stage following MCI and characterized by full-blown dementia; however, information involving EAD is limited. Oxidative stress is well-established in MCI and AD, including protein oxidation. Protein nitration also is an important oxidative modification observed in MCI and AD, and proteomic analysis from our laboratory identified nitrated proteins in both MCI and AD. Therefore, in the current study, a proteomics approach was used to identify nitrated brain proteins in the inferior parietal lobule from four subjects with EAD. Eight proteins were found to be significantly nitrated in EAD: peroxiredoxin 2, triose phosphate isomerase, glutamate dehydrogenase, neuropolypeptide h3, phosphoglycerate mutase1, H(+)- transporting ATPase, alpha-enolase and fructose-1,6-bisphosphate aldolase. Many of these proteins are also nitrated in MCI and late-stage AD, making this study the first to our knowledge to link nitrated proteins in all stages of AD. These results are discussed in terms of potential involvement in the progression of this dementing disorder.

Figure 1

3‐Nitrotyrosine levels in inferior parietal lobule indexed in early Alzheimer’s disease (EAD) and age‐matched control. Mean ± S.E.M. N = 4, P < 0.0.5.

Figure 2

Representative 2D gel images of IPL proteins from age‐matched control (A) and early Alzheimer’s disease (EAD) subjects (B).

Figure 2

Representative 2D gel images of IPL proteins from age‐matched control (A) and early Alzheimer’s disease (EAD) subjects (B).

Figure 3

Representative 2D Western blot of inferior parietal lobule probed with anti‐3‐nitrotyrosine for control (A) and early Alzheimer’s disease (EAD) (B).

Figure 3

Representative 2D Western blot of inferior parietal lobule probed with anti‐3‐nitrotyrosine for control (A) and early Alzheimer’s disease (EAD) (B).

Figure 4

Activity of ATP synthase in early Alzheimer’s disease (EAD) inferior parietal lobule compared with age‐matched control. Bars represent mean ± S.E.M, *P < 0.05; n= 4 for each group. ATP synthase activity is significantly decreased in EAD samples.

Figure 5

Reduced glutamate dehydrogenase activity in early Alzheimer’s disease (EAD) inferior parietal lobule compared with control.
Bars represent mean ± S.E.M, *P < 0.05; n= 4 for each group.

Figure 6

Venn diagram of functional relationship between nitrated proteins in mild cognitive impairment (MCI) early Alzheimer’s disease (EAD) and Alzheimer’s disease (AD).