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Loss of angiotensin II receptor expression in dopamine neurons in Parkinson's disease correlates with pathological progression and is accompanied by increases in Nox4- and 8-OH guanosine-related nucleic acid oxidation and caspase-3 activation.

Zawada WM, Mrak RE, Biedermann J, Palmer QD, Gentleman SM, Aboud O, Griffin WS - Acta Neuropathol Commun (2015)

Bottom Line: The proportional increase in nuclear AT1 in dopamine neurons in nigrosome 1 of prePD and PD patients was accompanied by elevated nuclear expression of Nox4, oxidative damage to DNA, and caspase-3-mediated cell loss.Our observations are consistent with the idea that AngII/AT1/Nox4 axis-mediated oxidative stress gives rise to the dopamine neuron dysfunction and loss characteristic of the neuropathological and clinical manifestations of PD and suggest that the chance for a neuron to survive increases in association with lower total as well as nuclear AT1 expression.Our results support the need for further evaluation of ARBs as disease-modifying agents in PD.

View Article: PubMed Central - PubMed

ABSTRACT

Background: In rodent models of Parkinson's disease (PD), dopamine neuron loss is accompanied by increased expression of angiotensin II (AngII), its type 1 receptor (AT1), and NADPH oxidase (Nox) in the nigral dopamine neurons and microglia. AT1 blockers (ARBs) stymie such oxidative damage and neuron loss. Whether changes in the AngII/AT1/Nox4 axis contribute to Parkinson neuropathogenesis is unknown. Here, we studied the distribution of AT1 and Nox4 in dopamine neurons in two nigral subregions: the less affected calbindin-rich matrix and the first-affected calbindin-poor nigrosome 1 of three patients, who were clinically asymptomatic, but had nigral dopamine cell loss and Braak stages consistent with a neuropathological diagnosis of PD (prePD). For comparison, five clinically- and neuropathologically-confirmed PD patients and seven age-matched control patients (AMC) were examined.

Results: AT1 and Nox4 immunoreactivity was noted in dopamine neurons in both the matrix and the nigrosome 1. The total cellular levels of AT1 in surviving dopamine neurons in the matrix and nigrosome 1 declined from AMC>prePD>PD, suggesting that an AngII/AT1/Nox4 axis orders neurodegenerative progression. In this vein, the loss of dopamine neurons was paralleled by a decline in total AT1 per surviving dopamine neuron. Similarly, AT1 in the nuclei of surviving neurons in the nigral matrix declined with disease progression, i.e., AMC>prePD>PD. In contrast, in nigrosome 1, the expression of nuclear AT1 was unaffected and similar in all groups. The ratio of nuclear AT1 to total AT1 (nuclear + cytoplasmic + membrane) in dopamine neurons increased stepwise from AMC to prePD to PD. The proportional increase in nuclear AT1 in dopamine neurons in nigrosome 1 of prePD and PD patients was accompanied by elevated nuclear expression of Nox4, oxidative damage to DNA, and caspase-3-mediated cell loss.

Conclusions: Our observations are consistent with the idea that AngII/AT1/Nox4 axis-mediated oxidative stress gives rise to the dopamine neuron dysfunction and loss characteristic of the neuropathological and clinical manifestations of PD and suggest that the chance for a neuron to survive increases in association with lower total as well as nuclear AT1 expression. Our results support the need for further evaluation of ARBs as disease-modifying agents in PD.

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Activation of caspase-3 corresponds to severity of PD. Immunodetection of active caspase-3 in TH-immunoreactive dopamine neurons in the SN of AMC (A-C), prePD (D-F), and PD (G-I) patients. In an AMC case (A), arrow identifies a dopamine neuron immunopositive for active caspase-3 in an area otherwise containing little active caspase-3. In addition, depicted are magnified views of subcellular localization of active caspase-3 in reference to the nuclei (B, E, H) as well as of individual neurons in merged images (C, F, I). Panel (I), contains an additional inset at the magnification of the main panel (I) illustrating vividly the boundaries of the DAPI-positive nucleus within a TH-immunoreactive dopamine neuron to more clearly depict the extent of active caspase-3 labelling within the nucleus. Scale bar equals 50 μm (A, D, and G) or 18 μm (B, C, E, F, H, I, and inset in I). Asterisks in (C, F, and I) identify neuromelanin.
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Fig8: Activation of caspase-3 corresponds to severity of PD. Immunodetection of active caspase-3 in TH-immunoreactive dopamine neurons in the SN of AMC (A-C), prePD (D-F), and PD (G-I) patients. In an AMC case (A), arrow identifies a dopamine neuron immunopositive for active caspase-3 in an area otherwise containing little active caspase-3. In addition, depicted are magnified views of subcellular localization of active caspase-3 in reference to the nuclei (B, E, H) as well as of individual neurons in merged images (C, F, I). Panel (I), contains an additional inset at the magnification of the main panel (I) illustrating vividly the boundaries of the DAPI-positive nucleus within a TH-immunoreactive dopamine neuron to more clearly depict the extent of active caspase-3 labelling within the nucleus. Scale bar equals 50 μm (A, D, and G) or 18 μm (B, C, E, F, H, I, and inset in I). Asterisks in (C, F, and I) identify neuromelanin.

Mentions: The degree of activation of the AT1 → Nox4 → superoxide cascade correlated with immunodetection of heightened levels of activated caspase-3, a surrogate for an irreversible step in the apoptotic cell death pathway. In the aged human brain, we have observed a continuum of active caspase-3 phenotypes, such that most of the neurologically normal control individuals demonstrated some, albeit typically low, levels of active caspase-3 in dopamine neurons (Figure 8A-C), while in prePD and PD cases dopamine neurons displayed more intense fluorescence of active caspase-3 (Figure 8D-I). The distribution of active caspase-3 between the cytoplasmic and the nuclear compartments was also heterogeneous (Figure 8) indicating that age-related stresses affect caspase-3 activation status in humans.Figure 8


Loss of angiotensin II receptor expression in dopamine neurons in Parkinson's disease correlates with pathological progression and is accompanied by increases in Nox4- and 8-OH guanosine-related nucleic acid oxidation and caspase-3 activation.

Zawada WM, Mrak RE, Biedermann J, Palmer QD, Gentleman SM, Aboud O, Griffin WS - Acta Neuropathol Commun (2015)

Activation of caspase-3 corresponds to severity of PD. Immunodetection of active caspase-3 in TH-immunoreactive dopamine neurons in the SN of AMC (A-C), prePD (D-F), and PD (G-I) patients. In an AMC case (A), arrow identifies a dopamine neuron immunopositive for active caspase-3 in an area otherwise containing little active caspase-3. In addition, depicted are magnified views of subcellular localization of active caspase-3 in reference to the nuclei (B, E, H) as well as of individual neurons in merged images (C, F, I). Panel (I), contains an additional inset at the magnification of the main panel (I) illustrating vividly the boundaries of the DAPI-positive nucleus within a TH-immunoreactive dopamine neuron to more clearly depict the extent of active caspase-3 labelling within the nucleus. Scale bar equals 50 μm (A, D, and G) or 18 μm (B, C, E, F, H, I, and inset in I). Asterisks in (C, F, and I) identify neuromelanin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4359535&req=5

Fig8: Activation of caspase-3 corresponds to severity of PD. Immunodetection of active caspase-3 in TH-immunoreactive dopamine neurons in the SN of AMC (A-C), prePD (D-F), and PD (G-I) patients. In an AMC case (A), arrow identifies a dopamine neuron immunopositive for active caspase-3 in an area otherwise containing little active caspase-3. In addition, depicted are magnified views of subcellular localization of active caspase-3 in reference to the nuclei (B, E, H) as well as of individual neurons in merged images (C, F, I). Panel (I), contains an additional inset at the magnification of the main panel (I) illustrating vividly the boundaries of the DAPI-positive nucleus within a TH-immunoreactive dopamine neuron to more clearly depict the extent of active caspase-3 labelling within the nucleus. Scale bar equals 50 μm (A, D, and G) or 18 μm (B, C, E, F, H, I, and inset in I). Asterisks in (C, F, and I) identify neuromelanin.
Mentions: The degree of activation of the AT1 → Nox4 → superoxide cascade correlated with immunodetection of heightened levels of activated caspase-3, a surrogate for an irreversible step in the apoptotic cell death pathway. In the aged human brain, we have observed a continuum of active caspase-3 phenotypes, such that most of the neurologically normal control individuals demonstrated some, albeit typically low, levels of active caspase-3 in dopamine neurons (Figure 8A-C), while in prePD and PD cases dopamine neurons displayed more intense fluorescence of active caspase-3 (Figure 8D-I). The distribution of active caspase-3 between the cytoplasmic and the nuclear compartments was also heterogeneous (Figure 8) indicating that age-related stresses affect caspase-3 activation status in humans.Figure 8

Bottom Line: The proportional increase in nuclear AT1 in dopamine neurons in nigrosome 1 of prePD and PD patients was accompanied by elevated nuclear expression of Nox4, oxidative damage to DNA, and caspase-3-mediated cell loss.Our observations are consistent with the idea that AngII/AT1/Nox4 axis-mediated oxidative stress gives rise to the dopamine neuron dysfunction and loss characteristic of the neuropathological and clinical manifestations of PD and suggest that the chance for a neuron to survive increases in association with lower total as well as nuclear AT1 expression.Our results support the need for further evaluation of ARBs as disease-modifying agents in PD.

View Article: PubMed Central - PubMed

ABSTRACT

Background: In rodent models of Parkinson's disease (PD), dopamine neuron loss is accompanied by increased expression of angiotensin II (AngII), its type 1 receptor (AT1), and NADPH oxidase (Nox) in the nigral dopamine neurons and microglia. AT1 blockers (ARBs) stymie such oxidative damage and neuron loss. Whether changes in the AngII/AT1/Nox4 axis contribute to Parkinson neuropathogenesis is unknown. Here, we studied the distribution of AT1 and Nox4 in dopamine neurons in two nigral subregions: the less affected calbindin-rich matrix and the first-affected calbindin-poor nigrosome 1 of three patients, who were clinically asymptomatic, but had nigral dopamine cell loss and Braak stages consistent with a neuropathological diagnosis of PD (prePD). For comparison, five clinically- and neuropathologically-confirmed PD patients and seven age-matched control patients (AMC) were examined.

Results: AT1 and Nox4 immunoreactivity was noted in dopamine neurons in both the matrix and the nigrosome 1. The total cellular levels of AT1 in surviving dopamine neurons in the matrix and nigrosome 1 declined from AMC>prePD>PD, suggesting that an AngII/AT1/Nox4 axis orders neurodegenerative progression. In this vein, the loss of dopamine neurons was paralleled by a decline in total AT1 per surviving dopamine neuron. Similarly, AT1 in the nuclei of surviving neurons in the nigral matrix declined with disease progression, i.e., AMC>prePD>PD. In contrast, in nigrosome 1, the expression of nuclear AT1 was unaffected and similar in all groups. The ratio of nuclear AT1 to total AT1 (nuclear + cytoplasmic + membrane) in dopamine neurons increased stepwise from AMC to prePD to PD. The proportional increase in nuclear AT1 in dopamine neurons in nigrosome 1 of prePD and PD patients was accompanied by elevated nuclear expression of Nox4, oxidative damage to DNA, and caspase-3-mediated cell loss.

Conclusions: Our observations are consistent with the idea that AngII/AT1/Nox4 axis-mediated oxidative stress gives rise to the dopamine neuron dysfunction and loss characteristic of the neuropathological and clinical manifestations of PD and suggest that the chance for a neuron to survive increases in association with lower total as well as nuclear AT1 expression. Our results support the need for further evaluation of ARBs as disease-modifying agents in PD.

Show MeSH
Related in: MedlinePlus