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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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Ratio of nuclear to total AT1 in TH+ neurons. The ratio was calculated by dividing the average AT1 immunofluorescence intensity measured in the nuclei of TH+ neurons by that measured from the entire TH+ neurons in neurologically intact individuals/AMC and in prePD and in PD patients.
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Fig6: Ratio of nuclear to total AT1 in TH+ neurons. The ratio was calculated by dividing the average AT1 immunofluorescence intensity measured in the nuclei of TH+ neurons by that measured from the entire TH+ neurons in neurologically intact individuals/AMC and in prePD and in PD patients.

Mentions: Although AT1 immunoreactivity was most evident in dopamine neurons, it was also present in non-TH-immunoreactive neural cells, and this immunoreactivity followed a most-to-least order from perinuclear, to cytoplasmic, to intranuclear (Figure 5A-B). Many nuclei of dopamine neurons, particularly in tissues from PD and prePD patients, exhibited AT1 accumulations, which appeared to penetrate the nucleus and coincide with irregularly-shaped nuclei (Figure 5C). In addition to this apparent intranuclear localization, AT1 was also noted within the nuclear envelope as evidenced by co-localization of AT1 immunoreactivity with an integral subunit of the nuclear pore complex, nucleoporin p62 [29,30] (Figure 5D-G). AT1 co-localized with p62 in neurons and numerous smaller cells in all AMC, prePD, and PD cases examined. Quantification of AT1 immunofluorescence within nuclei of dopamine neurons in neurologically intact individuals/AMC and in prePD and in PD patients (Figure 5H) showed that the density of nuclear AT1 in nigrosome 1 remains constant as disease progresses whereas, in the matrix, the abundance of nuclear AT1 is gradually reduced as a function of disease progression following the trajectory of the total AT1 decline within the entire neuron (Figure 4I). Consequently, the ratio of nuclear AT1 to total AT1 (nuclear + cytoplasmic + membrane) in dopamine neurons of nigrosome 1 (Figure 6) increased stepwise from AMC (0.274) → prePD (0.311) → PD (0.305). The increase in the ratio was more gradual in the matrix (Figure 6), as compared with the nigrosome, demonstrating the following pattern of increases: AMC (0.270) → prePD (0.290) → PD (0.305).Figure 5


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)

Ratio of nuclear to total AT1 in TH+ neurons. The ratio was calculated by dividing the average AT1 immunofluorescence intensity measured in the nuclei of TH+ neurons by that measured from the entire TH+ neurons in neurologically intact individuals/AMC and in prePD and in PD patients.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig6: Ratio of nuclear to total AT1 in TH+ neurons. The ratio was calculated by dividing the average AT1 immunofluorescence intensity measured in the nuclei of TH+ neurons by that measured from the entire TH+ neurons in neurologically intact individuals/AMC and in prePD and in PD patients.
Mentions: Although AT1 immunoreactivity was most evident in dopamine neurons, it was also present in non-TH-immunoreactive neural cells, and this immunoreactivity followed a most-to-least order from perinuclear, to cytoplasmic, to intranuclear (Figure 5A-B). Many nuclei of dopamine neurons, particularly in tissues from PD and prePD patients, exhibited AT1 accumulations, which appeared to penetrate the nucleus and coincide with irregularly-shaped nuclei (Figure 5C). In addition to this apparent intranuclear localization, AT1 was also noted within the nuclear envelope as evidenced by co-localization of AT1 immunoreactivity with an integral subunit of the nuclear pore complex, nucleoporin p62 [29,30] (Figure 5D-G). AT1 co-localized with p62 in neurons and numerous smaller cells in all AMC, prePD, and PD cases examined. Quantification of AT1 immunofluorescence within nuclei of dopamine neurons in neurologically intact individuals/AMC and in prePD and in PD patients (Figure 5H) showed that the density of nuclear AT1 in nigrosome 1 remains constant as disease progresses whereas, in the matrix, the abundance of nuclear AT1 is gradually reduced as a function of disease progression following the trajectory of the total AT1 decline within the entire neuron (Figure 4I). Consequently, the ratio of nuclear AT1 to total AT1 (nuclear + cytoplasmic + membrane) in dopamine neurons of nigrosome 1 (Figure 6) increased stepwise from AMC (0.274) → prePD (0.311) → PD (0.305). The increase in the ratio was more gradual in the matrix (Figure 6), as compared with the nigrosome, demonstrating the following pattern of increases: AMC (0.270) → prePD (0.290) → PD (0.305).Figure 5

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