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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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Nigrosomes at specific rostrocaudal levels of the adult human SN. Nigrosomes were identified in all 15 patients examined by Calbindin D28k immunohistochemistry in the intermediate (A, C, and E) and caudal (B, D, and F) SN. In these negative images, nigrosomes are depicted as dark areas (i.e., calbindin-poor) and numbered 1–4. Matrix is calbindin-rich and appears white. We have examined one AOI for nigrosome 1 and another AOI for matrix for each case studied. Substantia nigra (SN); Red nucleus (RN). Scale bar is 1000 μm.
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Fig1: Nigrosomes at specific rostrocaudal levels of the adult human SN. Nigrosomes were identified in all 15 patients examined by Calbindin D28k immunohistochemistry in the intermediate (A, C, and E) and caudal (B, D, and F) SN. In these negative images, nigrosomes are depicted as dark areas (i.e., calbindin-poor) and numbered 1–4. Matrix is calbindin-rich and appears white. We have examined one AOI for nigrosome 1 and another AOI for matrix for each case studied. Substantia nigra (SN); Red nucleus (RN). Scale bar is 1000 μm.

Mentions: Brains were fixed in formalin (no methanol) for two weeks prior to further processing. Formalin-fixed midbrain was blocked in a transverse plane and paraffin-embedded prior to cutting 7 μm-thick sections of the substantia nigra at its intermediate to caudal levels and processed as previously described [26]. The intermediate substantia nigra was defined as that coinciding with the exit of Cranial Nerve III. All antibodies used, clone (m = monoclonal) or type (p = polyclonal), recognized epitope(s), methods for unmasking epitopes, dilutions, and procurement sources are listed in Table 2. The primary antibody for AT1 detection was a goat IgG from Santa Cruz (Cat# sc-1173-G). For each case, at least six sections from substantia nigra were cut, and at least one section immunostained for each of the following: i) TH/AT1/DAPI; ii) Nox4/AT1/DAPI; iii) StressMarq/AT1/DAPI; iv) caspase-3/TH/DAPI; v) α-synuclein; and vi) calbindin D28k. For select AMC, prePD, and PD cases additional sections were cut and processed for co-immunodetection of AT1 with one of the following GFAP, Iba1, Nup62, Pan-Neuronal whole neuron marker, or S100B. Calbindin D28k immunohistochemistry was used to identify nigrosomes in all 15 patients examined. Photomicrographs demonstrating position of nigrosomes 1–4, located in intermediate and caudal substantia nigra are identifiable as dark areas, i.e., calbindin-poor regions adjacent to bright areas that are calbindin rich (Figure 1).Table 2


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)

Nigrosomes at specific rostrocaudal levels of the adult human SN. Nigrosomes were identified in all 15 patients examined by Calbindin D28k immunohistochemistry in the intermediate (A, C, and E) and caudal (B, D, and F) SN. In these negative images, nigrosomes are depicted as dark areas (i.e., calbindin-poor) and numbered 1–4. Matrix is calbindin-rich and appears white. We have examined one AOI for nigrosome 1 and another AOI for matrix for each case studied. Substantia nigra (SN); Red nucleus (RN). Scale bar is 1000 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Nigrosomes at specific rostrocaudal levels of the adult human SN. Nigrosomes were identified in all 15 patients examined by Calbindin D28k immunohistochemistry in the intermediate (A, C, and E) and caudal (B, D, and F) SN. In these negative images, nigrosomes are depicted as dark areas (i.e., calbindin-poor) and numbered 1–4. Matrix is calbindin-rich and appears white. We have examined one AOI for nigrosome 1 and another AOI for matrix for each case studied. Substantia nigra (SN); Red nucleus (RN). Scale bar is 1000 μm.
Mentions: Brains were fixed in formalin (no methanol) for two weeks prior to further processing. Formalin-fixed midbrain was blocked in a transverse plane and paraffin-embedded prior to cutting 7 μm-thick sections of the substantia nigra at its intermediate to caudal levels and processed as previously described [26]. The intermediate substantia nigra was defined as that coinciding with the exit of Cranial Nerve III. All antibodies used, clone (m = monoclonal) or type (p = polyclonal), recognized epitope(s), methods for unmasking epitopes, dilutions, and procurement sources are listed in Table 2. The primary antibody for AT1 detection was a goat IgG from Santa Cruz (Cat# sc-1173-G). For each case, at least six sections from substantia nigra were cut, and at least one section immunostained for each of the following: i) TH/AT1/DAPI; ii) Nox4/AT1/DAPI; iii) StressMarq/AT1/DAPI; iv) caspase-3/TH/DAPI; v) α-synuclein; and vi) calbindin D28k. For select AMC, prePD, and PD cases additional sections were cut and processed for co-immunodetection of AT1 with one of the following GFAP, Iba1, Nup62, Pan-Neuronal whole neuron marker, or S100B. Calbindin D28k immunohistochemistry was used to identify nigrosomes in all 15 patients examined. Photomicrographs demonstrating position of nigrosomes 1–4, located in intermediate and caudal substantia nigra are identifiable as dark areas, i.e., calbindin-poor regions adjacent to bright areas that are calbindin rich (Figure 1).Table 2

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