Oxidative stress and hippocampal synaptic protein levels in elderly cognitively intact individuals with Alzheimer's disease pathology - PubMed (original) (raw)

Oxidative stress and hippocampal synaptic protein levels in elderly cognitively intact individuals with Alzheimer's disease pathology

Stephen W Scheff et al. Neurobiol Aging. 2016 Jun.

Abstract

Neuritic amyloid plaques and neurofibrillary tangles are hallmarks of Alzheimer's disease (AD) and are major components used for the clinical diagnosis of this disorder. However, many individuals with no cognitive impairment (NCI) also present at autopsy with high levels of these AD pathologic hallmarks. In this study, we evaluated 15 autopsy cases from NCI individuals with high levels of AD-like pathology (high pathology no cognitive impairment) and compared them to age- and postmortem-matched cohorts of individuals with amnestic mild cognitive impairment and NCI cases with low AD-like pathology (low pathology no cognitive impairment [LPNCI]). Individuals classified as high pathology no cognitive impairment or amnestic mild cognitive impairment had a significant loss of both presynaptic and postsynaptic proteins in the hippocampus compared with those in the LPNCI cohort. In addition, these 2 groups had a significant increase in 3 different markers of oxidative stress compared with that in the LPNCI group. The changes in levels of synaptic proteins are strongly associated with levels of oxidative stress. These data suggest that cognitively older subjects without dementia but with increased levels of AD-like pathology may represent a very early preclinical stage of AD.

Keywords: Aging; Amyloid; Dementia; Hippocampus; Neurodegeneration; Synapses; Temporal lobe.

Copyright © 2016 Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1

Changes in synaptic protein levels in the hippocampus. Five different synaptic proteins (2 presynaptic and 3 postsynaptic) were analyzed by Western blot with beta actin used as a loading control on the gels (A). Scatter plots showing changes in different synaptic proteins within the hippocampus for each subject from the different cohorts representing different possible stages in the progression of the disease: Low pathology no cognitive impairment (LPNCI), high pathology no cognitive impairment (HPNCI), amnestic mild cognitive impairment (aMCI). (B) Antibodies directed against presynaptic proteins synapsin-1 and synaptophysin are shown. (C) Antibodies directed against postsynaptic proteins drebrin, SAP-97, and PSD-95. Horizontal lines indicate group medians. *p<0.05, **p<0.01, ***p<0.005, #p<0.001 compared to LPNCI.

Figure 2

Figure 2

Representative slot-blots for (A) protein carbonyl, (B) 4-hydroxynonenal, and (C) 3-nitrotyrosine fractions from the hippocampus from individuals classified as no cognitive impairment and low AD-like pathology (LP-NCI), no cognitive impairment and high AD-like pathology (HP-NCI), and amnestic mild cognitive impairment (aMCI). The slot-blot shows alterations in staining for the different cohorts for each of the different markers of oxidative stress.

Figure 3

Figure 3

Scatterplots showing changes in the markers of hippocampal oxidative stress among the different cohorts in the present study. The low pathology no cognitive impairment (LPNCI) cohort consistently demonstrated significantly lower levels of oxidative stress compared to the high pathology no cognitive impairment (HPNCI) and amnestic mild cognitive impairment (aMCI) groups for all three of the different markers of oxidative stress. Horizontal lines indicate group medians. *p<0.01, **p<0.001 compared to LPNCI, #p<0.001 compared to HPNCI.

Figure 4

Figure 4

Correlations between different synaptic proteins and markers of oxidative stress in the hippocampus. Almost every comparison showed a negative association between levels of oxidative stress and the levels of various synaptic proteins. One exception was the lack of any observed association between levels of protein carbonyls and levels of the presynaptic marker synaptophysin. Abbreviations: AD, arbitrary units; PSD-95, postsynaptic density-95; SAP-97, synapse associated proteins 97.

Figure 5

Figure 5

Scatterplots showing the levels of soluble Aβ1-42 in the hippocampus as a function of the different cohorts evaluated. There was no significant difference observed between the two groups with individuals labeled as no cognitive impairment (NCI) (p > 0.1). However, both the low pathology and high pathology NCI groups were significantly lower than the amnestic mild cognitive impairment (aMCI) cohort. Horizontal lines indicate group medians. *p<0.05

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