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

Scheff, Stephen W.; Ansari, Mubeen A.; Mufson, Elliott J.

doi:10.1016/j.neurobiolaging.2016.02.030

Cited by 77 publications

(53 citation statements)

References 130 publications

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“…8) in the context of AD-associated hippocampal volume loss might be elucidated in future correlative studies of MRI-measured HV and the presence of low HV -associated MSRB3 risk allele. MsrB3 may influence hippocampal volume in aging, AD and neurovascular diseases, which are all associated with increased oxidative stress[25–29]. …”

Section: Discussionmentioning

confidence: 99%

Methionine Sulfoxide Reductase-B3 (MsrB3) Protein Associates with Synaptic Vesicles and its Expression Changes in the Hippocampi of Alzheimer’s Disease Patients

Adams

Benayoun

Tilton

et al. 2017

JAD

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Genome-wide association studies (GWAS) identified susceptibility loci associated with decreased hippocampal volume, and found hippocampal subfield-specific effects at MSRB3 (methionine sulfoxide reductase-B3). The MSRB3 locus was also linked to increased risk for late onset Alzheimer’s disease (AD). In this study we uncovered novel sites of MsrB3 expression in CA pyramidal layer and arteriolar walls by using automated immunohistochemistry on hippocampal sections from 23 individuals accompanied by neuropathology reports and clinical dementia rating scores. Controls, cognitively intact subjects with no hippocampal neurofibrillary tangles, exhibited MsrB3 signal as distinct but rare puncta in CA1 pyramidal neuronal somata. In CA3, however, MsrB3-immunoreactivity was strongest in the neuropil of the pyramidal layer. These patterns were replicated in rodent hippocampi where ultrastructural and immunohistofluorescence analysis revealed MsrB3 signal associated with synaptic vesicles and colocalized with mossy fiber terminals. In AD subjects, the number of CA1 pyramidal neurons with frequent, rather than rare, MsrB3-immunoreactive somatic puncta increased in comparison to controls. This change in CA1 phenotype correlated with the occurrence of AD pathological hallmarks. Moreover, the intensity of MsrB3 signal in the neuropil of CA3 pyramidal layer correlated with the signal pattern in neurons of CA1 pyramidal layer that was characteristic of cognitively intact individuals. Finally, MsrB3 signal in the arteriolar walls in the hippocampal white matter decreased in AD patients. This characterization of GWAS-implicated MSRB3 protein expression in human hippocampus suggests that patterns of neuronal and vascular MsrB3 protein expression reflect or underlie pathology associated with Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 99%

Methionine Sulfoxide Reductase-B3 (MsrB3) Protein Associates with Synaptic Vesicles and its Expression Changes in the Hippocampi of Alzheimer’s Disease Patients

Adams

Benayoun

Tilton

et al. 2017

JAD

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“…Fourthly, apart from neurogenesis, the LRRK2 G2019S mutation is associated with impairment is several cellular and molecular mechanisms of learning and memory including dendritic arborization as well as the formation of spines and synaptic connections within the hippocampus (Winner et al, 2011). Synaptic protein loss correlates with, and may mark or precede the earliest stages of memory impairment (Counts et al, 2006; Proctor et al, 2010; Scheff, Ansari, & Mufson, 2016; Sze et al, 1997; Yuki et al, 2014). We specifically addressed this point in this study by assessing synaptic protein expression in the hippocampus of the mice where LRRK2 is most highly expressed in the brain (Melrose et al, 2010; Winner et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Human LRRK2 G2019S mutation represses post-synaptic protein PSD95 and causes cognitive impairment in transgenic mice

Adeosun

Hou

Zheng

et al. 2017

Neurobiology of Learning and Memory

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Background-LRRK2 G2019S mutation is associated with increased kinase activity and is the most common mutation associated with late-onset PD. However, the transgenic mouse model has not recapitulated cardinal PD-related motor phenotypes. Non-motor symptoms of PD including cognitive impairments are very common and may appear earlier than the motor symptoms. The objective of this study was to determine whether human LRRK2 with G2019S mutation causes hippocampus-dependent cognitive deficits in mice.Results-Male (LRRK2-G2019S) LRRK2-Tg mice showed impairments in the early portion of the Two-day radial arm water maze acquisition trial as well as in the reversal learning on the third day. However, their performance was similar to Non-Tg controls in the probe trial. LRRK2-Tg mice also displayed impairments in the novel arm discrimination test but not in the spontaneous alternation test in Y-maze. Interestingly, there was no statistically significant locomotor impairment during any of these cognitive test, nor in the locomotor tests including open field, accelerating rotarod and pole tests. Expression of the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin was lower in hippocampal homogenates of LRRK2-Tg mice.Conclusion-Consistent with previous reports in human LRRK2 G2019S carriers, the current data suggests that cognitive dysfunctions are present in LRRK2-Tg mice even in the absence of locomotor impairment. LRRK2 G2019S mutation represses the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin. This study also suggests that mild cognitive impairment may appear earlier than motor dysfunctions in LRRK2-G2019S mutation carriers.

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“…But, regardless of the specific cellular mechanism, our data provide proof-of-concept that CN hyperactivity in astrocytes, especially in areas of amyloid and vascular pathology (as shown with the ΔCN antibody, see Figures 2–4), can have deleterious effects on synapses. Whether the proteolysis of CN is directly linked to the striking synapse loss that occurs with AD [86–88] and VCID [89] is still unknown and will need to be determined.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function

Pleiss¹,

Sompol²,

Kraner³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Mounting evidence suggests that astrocyte activation, found in most forms of neural injury and disease, is linked to the hyperactivation of the protein phosphatase calcineurin. In many tissues and cell types, calcineurin hyperactivity is the direct result of limited proteolysis. However, little is known about the proteolytic status of calcineurin in activated astrocytes. Here, we developed a polyclonal antibody to a high activity calcineurin proteolytic fragment in the 45–48 kDa range (ΔCN) for use in immunohistochemical applications. When applied to postmortem human brain sections, the ΔCN antibody intensely labeled cell clusters in close juxtaposition to amyloid deposits and microinfarcts. Many of these cells exhibited clear activated astrocyte morphology. The expression of ΔCN in astrocytes near areas of pathology was further confirmed using confocal microscopy. Multiple NeuN-positive cells, particularly those within microinfarct core regions, also labeled positively for ΔCN. This observation suggests that calcineurin proteolysis can also occur within damaged or dying neurons, as reported in other studies. When a similar ΔCN fragment was selectively expressed in hippocampal astrocytes of intact rats (using adeno-associated virus), we observed a significant reduction in the strength of CA3-CA1 excitatory synapses, indicating that the hyperactivation of astrocytic calcineurin is sufficient for disrupting synaptic function. Together, these results suggest that proteolytic activation of calcineurin in activated astrocytes may be a central mechanism for driving and/or exacerbating neural dysfunction during neurodegenerative disease and injury.

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

Cited by 77 publications

References 130 publications

Methionine Sulfoxide Reductase-B3 (MsrB3) Protein Associates with Synaptic Vesicles and its Expression Changes in the Hippocampi of Alzheimer’s Disease Patients

Methionine Sulfoxide Reductase-B3 (MsrB3) Protein Associates with Synaptic Vesicles and its Expression Changes in the Hippocampi of Alzheimer’s Disease Patients

Human LRRK2 G2019S mutation represses post-synaptic protein PSD95 and causes cognitive impairment in transgenic mice

Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function

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