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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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A cell type-dependent model of interactions between AT1 and Nox1, 2, and 4 in the human substantia nigra. The AT1 is broadly expressed in the CNS in astrocytes, microglia, and is particularly abundant in neurons, including dopamine neurons where, as we demonstrate here, the AT1 is found not only on the plasma membrane, but also intracellularly associated with the membranes of the endoplasmic reticulum, other cytoplasmic structures, nuclear membrane, and AT1 is found inside the nuclei themselves. The AT1 is also expressed by the vascular smooth muscle cells and by neutrophils and macrophages, raising the possibility that brain RAS activities can be influenced by the entry of peripheral monocyte-derived cells that are rich in AT1 and Nox2. The nuclear AT1, which we demonstrate here to be co-localized with nuclear Nox4, an event which frequency increases with disease progression, induces intra-nuclear production of reactive oxygen species (ROS, superoxide and hydrogen peroxide) leading to an increase in nucleic acid oxidation determined by increased levels of oxidized 8-OH guanosine (8-OHg). This complex landscape of AT1-Nox interactions, when balanced serves to maintain tissue homeostasis and normal levels of dopamine, but in chronic disease such as Parkinson’s the AngII/AT1/Nox4 axis might become overactive and lead to deleterious nucleic acid lesions that destabilize DNA and impair the transcriptional machinery in the affected neurons. Taken together, our findings suggest need for additional studies of these interactions toward designing therapies that restore healthy balance between the injurious and physiological functions of AT1 and Nox4 and by doing so moderate progression or prevent onset of neurodegenerative diseases. Legend: neurons – Nox4 (red), microglia – Nox2 (green), and astrocytes – mixture of Nox1 (yellow), Nox2 (green), and Nox4 (red).
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Fig9: A cell type-dependent model of interactions between AT1 and Nox1, 2, and 4 in the human substantia nigra. The AT1 is broadly expressed in the CNS in astrocytes, microglia, and is particularly abundant in neurons, including dopamine neurons where, as we demonstrate here, the AT1 is found not only on the plasma membrane, but also intracellularly associated with the membranes of the endoplasmic reticulum, other cytoplasmic structures, nuclear membrane, and AT1 is found inside the nuclei themselves. The AT1 is also expressed by the vascular smooth muscle cells and by neutrophils and macrophages, raising the possibility that brain RAS activities can be influenced by the entry of peripheral monocyte-derived cells that are rich in AT1 and Nox2. The nuclear AT1, which we demonstrate here to be co-localized with nuclear Nox4, an event which frequency increases with disease progression, induces intra-nuclear production of reactive oxygen species (ROS, superoxide and hydrogen peroxide) leading to an increase in nucleic acid oxidation determined by increased levels of oxidized 8-OH guanosine (8-OHg). This complex landscape of AT1-Nox interactions, when balanced serves to maintain tissue homeostasis and normal levels of dopamine, but in chronic disease such as Parkinson’s the AngII/AT1/Nox4 axis might become overactive and lead to deleterious nucleic acid lesions that destabilize DNA and impair the transcriptional machinery in the affected neurons. Taken together, our findings suggest need for additional studies of these interactions toward designing therapies that restore healthy balance between the injurious and physiological functions of AT1 and Nox4 and by doing so moderate progression or prevent onset of neurodegenerative diseases. Legend: neurons – Nox4 (red), microglia – Nox2 (green), and astrocytes – mixture of Nox1 (yellow), Nox2 (green), and Nox4 (red).

Mentions: While, overall, the total levels of AT1 decline in dopamine neurons from AMC to prePD to PD, dopamine neurons in nigrosome 1 differ in that the ratio of nuclear AT1 to total AT1 (nuclear + cytoplasmic + membrane) increased stepwise from AMC to prePD to PD. The mechanistic underpinnings of the proportional increase in nuclear AT1 in surviving dopamine neurons in nigrosome 1 of prePD and PD patients might be related to accompanying elevation in nuclear expression of superoxide-generating Nox4, which in turn may explain our finding of increased oxidative damage to DNA as measured by elevated 8-OH guanosine (summarized in Figure 9) and ongoing caspase-3-mediated proteolysis and cell death. The increase in the percent of Nox4+ and StressMarq + nuclei in the context of unchanging (or even declining in the matrix) AT1 expression might represent a compensatory mechanism, by which cellular stresses imposed on the dopamine neurons that might be directly or indirectly related to changes in AT1 expression promote increases in Nox4, which is known to be transcriptionally activated by stress and AngII [12].Figure 9


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)

A cell type-dependent model of interactions between AT1 and Nox1, 2, and 4 in the human substantia nigra. The AT1 is broadly expressed in the CNS in astrocytes, microglia, and is particularly abundant in neurons, including dopamine neurons where, as we demonstrate here, the AT1 is found not only on the plasma membrane, but also intracellularly associated with the membranes of the endoplasmic reticulum, other cytoplasmic structures, nuclear membrane, and AT1 is found inside the nuclei themselves. The AT1 is also expressed by the vascular smooth muscle cells and by neutrophils and macrophages, raising the possibility that brain RAS activities can be influenced by the entry of peripheral monocyte-derived cells that are rich in AT1 and Nox2. The nuclear AT1, which we demonstrate here to be co-localized with nuclear Nox4, an event which frequency increases with disease progression, induces intra-nuclear production of reactive oxygen species (ROS, superoxide and hydrogen peroxide) leading to an increase in nucleic acid oxidation determined by increased levels of oxidized 8-OH guanosine (8-OHg). This complex landscape of AT1-Nox interactions, when balanced serves to maintain tissue homeostasis and normal levels of dopamine, but in chronic disease such as Parkinson’s the AngII/AT1/Nox4 axis might become overactive and lead to deleterious nucleic acid lesions that destabilize DNA and impair the transcriptional machinery in the affected neurons. Taken together, our findings suggest need for additional studies of these interactions toward designing therapies that restore healthy balance between the injurious and physiological functions of AT1 and Nox4 and by doing so moderate progression or prevent onset of neurodegenerative diseases. Legend: neurons – Nox4 (red), microglia – Nox2 (green), and astrocytes – mixture of Nox1 (yellow), Nox2 (green), and Nox4 (red).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359535&req=5

Fig9: A cell type-dependent model of interactions between AT1 and Nox1, 2, and 4 in the human substantia nigra. The AT1 is broadly expressed in the CNS in astrocytes, microglia, and is particularly abundant in neurons, including dopamine neurons where, as we demonstrate here, the AT1 is found not only on the plasma membrane, but also intracellularly associated with the membranes of the endoplasmic reticulum, other cytoplasmic structures, nuclear membrane, and AT1 is found inside the nuclei themselves. The AT1 is also expressed by the vascular smooth muscle cells and by neutrophils and macrophages, raising the possibility that brain RAS activities can be influenced by the entry of peripheral monocyte-derived cells that are rich in AT1 and Nox2. The nuclear AT1, which we demonstrate here to be co-localized with nuclear Nox4, an event which frequency increases with disease progression, induces intra-nuclear production of reactive oxygen species (ROS, superoxide and hydrogen peroxide) leading to an increase in nucleic acid oxidation determined by increased levels of oxidized 8-OH guanosine (8-OHg). This complex landscape of AT1-Nox interactions, when balanced serves to maintain tissue homeostasis and normal levels of dopamine, but in chronic disease such as Parkinson’s the AngII/AT1/Nox4 axis might become overactive and lead to deleterious nucleic acid lesions that destabilize DNA and impair the transcriptional machinery in the affected neurons. Taken together, our findings suggest need for additional studies of these interactions toward designing therapies that restore healthy balance between the injurious and physiological functions of AT1 and Nox4 and by doing so moderate progression or prevent onset of neurodegenerative diseases. Legend: neurons – Nox4 (red), microglia – Nox2 (green), and astrocytes – mixture of Nox1 (yellow), Nox2 (green), and Nox4 (red).
Mentions: While, overall, the total levels of AT1 decline in dopamine neurons from AMC to prePD to PD, dopamine neurons in nigrosome 1 differ in that the ratio of nuclear AT1 to total AT1 (nuclear + cytoplasmic + membrane) increased stepwise from AMC to prePD to PD. The mechanistic underpinnings of the proportional increase in nuclear AT1 in surviving dopamine neurons in nigrosome 1 of prePD and PD patients might be related to accompanying elevation in nuclear expression of superoxide-generating Nox4, which in turn may explain our finding of increased oxidative damage to DNA as measured by elevated 8-OH guanosine (summarized in Figure 9) and ongoing caspase-3-mediated proteolysis and cell death. The increase in the percent of Nox4+ and StressMarq + nuclei in the context of unchanging (or even declining in the matrix) AT1 expression might represent a compensatory mechanism, by which cellular stresses imposed on the dopamine neurons that might be directly or indirectly related to changes in AT1 expression promote increases in Nox4, which is known to be transcriptionally activated by stress and AngII [12].Figure 9

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