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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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The number of TH-positive neurons counted in matrix and nigrosome 1 areas of SN in neurologically intact individuals (AMC) and in prePD and in PD patients. TH+ neurons were examined in two 9.0 mm2 areas of the SN, viz., in the matrix region, which is calbindin-rich, and nigrosome 1, a calbindin-poor region. Data are expressed as mean ± SEM; * denotes significant differences (p < 0.05) between nigrosome 1 in prePD and in PD as compared to AMC. The number of TH+ neurons in the matrix was not significantly altered with clinical diagnosis.
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Fig3: The number of TH-positive neurons counted in matrix and nigrosome 1 areas of SN in neurologically intact individuals (AMC) and in prePD and in PD patients. TH+ neurons were examined in two 9.0 mm2 areas of the SN, viz., in the matrix region, which is calbindin-rich, and nigrosome 1, a calbindin-poor region. Data are expressed as mean ± SEM; * denotes significant differences (p < 0.05) between nigrosome 1 in prePD and in PD as compared to AMC. The number of TH+ neurons in the matrix was not significantly altered with clinical diagnosis.

Mentions: The numbers of dopamine neurons in nigrosome 1 of prePD and in PD patients were markedly less (p = 0.002 and p < 0.001, respectively) than corresponding dopamine neuron counts in nigrosome 1 in AMC patients. Unlike the findings in nigrosome 1, the numbers of dopamine neurons in the matrix did not correlate with clinical diagnosis, although there was a trend toward reduction in these neurons in PD patients (Figure 3). These differences in cell loss between the matrix and nigrosome 1 suggest that the AT1 levels, distribution, and actions might also be differentially affected in neurons in these two nigral compartments, which is consistent with the view that the earliest signs of nigral dopamine neuron loss in Parkinson’s occur in the nigrosome 1 [23].Figure 3


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)

The number of TH-positive neurons counted in matrix and nigrosome 1 areas of SN in neurologically intact individuals (AMC) and in prePD and in PD patients. TH+ neurons were examined in two 9.0 mm2 areas of the SN, viz., in the matrix region, which is calbindin-rich, and nigrosome 1, a calbindin-poor region. Data are expressed as mean ± SEM; * denotes significant differences (p < 0.05) between nigrosome 1 in prePD and in PD as compared to AMC. The number of TH+ neurons in the matrix was not significantly altered with clinical diagnosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: The number of TH-positive neurons counted in matrix and nigrosome 1 areas of SN in neurologically intact individuals (AMC) and in prePD and in PD patients. TH+ neurons were examined in two 9.0 mm2 areas of the SN, viz., in the matrix region, which is calbindin-rich, and nigrosome 1, a calbindin-poor region. Data are expressed as mean ± SEM; * denotes significant differences (p < 0.05) between nigrosome 1 in prePD and in PD as compared to AMC. The number of TH+ neurons in the matrix was not significantly altered with clinical diagnosis.
Mentions: The numbers of dopamine neurons in nigrosome 1 of prePD and in PD patients were markedly less (p = 0.002 and p < 0.001, respectively) than corresponding dopamine neuron counts in nigrosome 1 in AMC patients. Unlike the findings in nigrosome 1, the numbers of dopamine neurons in the matrix did not correlate with clinical diagnosis, although there was a trend toward reduction in these neurons in PD patients (Figure 3). These differences in cell loss between the matrix and nigrosome 1 suggest that the AT1 levels, distribution, and actions might also be differentially affected in neurons in these two nigral compartments, which is consistent with the view that the earliest signs of nigral dopamine neuron loss in Parkinson’s occur in the nigrosome 1 [23].Figure 3

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