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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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Total cellular AT1 in SN dopamine neurons. (A-F) Immunodetected AT1 in the SN matrix (calbindin-rich area) from neurologically intact patients (AMC), from prePD patients, and from PD patients. (G and H) show an example of AT1 expression in nigrosome 1 (calbindin-poor area). Scale bar in (A-F) is 20 μm and in (G and H) is 10 μm. (I) Quantification of AT1 immunofluorescence in TH-immunopositive dopamine neurons in the SN matrix and in nigrosome 1 as well as images (A-F) clearly illustrate dramatic reduction in the AT1 expression in nigral dopamine neurons (most profound in the matrix) as disease progresses. In panel (I), a single asterisk identifies this AT1 immunofluorescence intensity measure as significantly different from the intensity measures in the other two matrix groups. The double asterisk indicates a significant difference between nigrosome 1 of AMC and PD.
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Fig4: Total cellular AT1 in SN dopamine neurons. (A-F) Immunodetected AT1 in the SN matrix (calbindin-rich area) from neurologically intact patients (AMC), from prePD patients, and from PD patients. (G and H) show an example of AT1 expression in nigrosome 1 (calbindin-poor area). Scale bar in (A-F) is 20 μm and in (G and H) is 10 μm. (I) Quantification of AT1 immunofluorescence in TH-immunopositive dopamine neurons in the SN matrix and in nigrosome 1 as well as images (A-F) clearly illustrate dramatic reduction in the AT1 expression in nigral dopamine neurons (most profound in the matrix) as disease progresses. In panel (I), a single asterisk identifies this AT1 immunofluorescence intensity measure as significantly different from the intensity measures in the other two matrix groups. The double asterisk indicates a significant difference between nigrosome 1 of AMC and PD.

Mentions: The observation by Ge and Barnes [21] of a significant reduction in ligand binding to the AT1 in tissue samples from the putamen, caudate, and substantia nigra of Parkinson’s patients as compared to such ligand binding in tissues from neurologically normal control patients aroused our suspicion that neurons might substantially contribute to such changes in the AT1 expression. We found that the intensity of AT1 immunoreactivity in surviving dopamine neurons in both matrix (Figure 4A-F) and in nigrosome 1 (Figure 4G and H) declined stepwise from neurologically intact patients in a disease-related fashion (AMC>prePD>PD). In fact, in dopamine neurons in nigral matrix of some patients with advanced PD, AT1 expression was almost non-existent (Figure 4C and F). A comparison of the expression of AT1 in dopamine neurons in nigral matrix and nigrosome 1 of tissue from control patients, or from either prePD or PD, demonstrated that the total AT1 immunofluorescence intensity per dopamine neuron was substantially reduced (p < 0.001) (Figure 4I).Figure 4


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)

Total cellular AT1 in SN dopamine neurons. (A-F) Immunodetected AT1 in the SN matrix (calbindin-rich area) from neurologically intact patients (AMC), from prePD patients, and from PD patients. (G and H) show an example of AT1 expression in nigrosome 1 (calbindin-poor area). Scale bar in (A-F) is 20 μm and in (G and H) is 10 μm. (I) Quantification of AT1 immunofluorescence in TH-immunopositive dopamine neurons in the SN matrix and in nigrosome 1 as well as images (A-F) clearly illustrate dramatic reduction in the AT1 expression in nigral dopamine neurons (most profound in the matrix) as disease progresses. In panel (I), a single asterisk identifies this AT1 immunofluorescence intensity measure as significantly different from the intensity measures in the other two matrix groups. The double asterisk indicates a significant difference between nigrosome 1 of AMC and PD.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Total cellular AT1 in SN dopamine neurons. (A-F) Immunodetected AT1 in the SN matrix (calbindin-rich area) from neurologically intact patients (AMC), from prePD patients, and from PD patients. (G and H) show an example of AT1 expression in nigrosome 1 (calbindin-poor area). Scale bar in (A-F) is 20 μm and in (G and H) is 10 μm. (I) Quantification of AT1 immunofluorescence in TH-immunopositive dopamine neurons in the SN matrix and in nigrosome 1 as well as images (A-F) clearly illustrate dramatic reduction in the AT1 expression in nigral dopamine neurons (most profound in the matrix) as disease progresses. In panel (I), a single asterisk identifies this AT1 immunofluorescence intensity measure as significantly different from the intensity measures in the other two matrix groups. The double asterisk indicates a significant difference between nigrosome 1 of AMC and PD.
Mentions: The observation by Ge and Barnes [21] of a significant reduction in ligand binding to the AT1 in tissue samples from the putamen, caudate, and substantia nigra of Parkinson’s patients as compared to such ligand binding in tissues from neurologically normal control patients aroused our suspicion that neurons might substantially contribute to such changes in the AT1 expression. We found that the intensity of AT1 immunoreactivity in surviving dopamine neurons in both matrix (Figure 4A-F) and in nigrosome 1 (Figure 4G and H) declined stepwise from neurologically intact patients in a disease-related fashion (AMC>prePD>PD). In fact, in dopamine neurons in nigral matrix of some patients with advanced PD, AT1 expression was almost non-existent (Figure 4C and F). A comparison of the expression of AT1 in dopamine neurons in nigral matrix and nigrosome 1 of tissue from control patients, or from either prePD or PD, demonstrated that the total AT1 immunofluorescence intensity per dopamine neuron was substantially reduced (p < 0.001) (Figure 4I).Figure 4

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