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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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Intracellular AT1 in neural and vascular cells of the adult human substantia nigra. AT1 is shown to be highly expressed in nigral dopamine neurons (A), in Iba1-positive microglia (B), and in S100B- (C) and GFAP-immunoreactive astrocytes (D-G) of a 69 years old prePD patient. AT1 is also detected in vascular smooth muscle cells in the tunica media (i.e., the medial layer) of the blood vessel wall (C). Scale bars are 20 μm.
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Fig2: Intracellular AT1 in neural and vascular cells of the adult human substantia nigra. AT1 is shown to be highly expressed in nigral dopamine neurons (A), in Iba1-positive microglia (B), and in S100B- (C) and GFAP-immunoreactive astrocytes (D-G) of a 69 years old prePD patient. AT1 is also detected in vascular smooth muscle cells in the tunica media (i.e., the medial layer) of the blood vessel wall (C). Scale bars are 20 μm.

Mentions: In all patients examined, irrespective of their health status (AMC, prePD, or PD), we found AT1 in all dopamine neurons. Adding prominence to the brain’s AT1 expression profile is the fact that AT1 was also expressed in all neurons as evidenced by the AT1 immunoreactivity present in neurons that were immunopositive for a Pan Neuronal marker, but were not pigmented and/or immunopositive for TH. An example of such neuronal AT1 expression is illustrated in a nigral section from a 69-year old prePD patient (Figure 2A). In addition, in all patients examined, AT1 immunoreactivity was present in both Iba1-immunoreactive microglia (Figure 2B) and S100B- and GFAP-immunoreactive astrocytes (Figure 2C-G). AT1 expression was also noted in vascular smooth muscle cells of the blood vessels within substantia nigra (Figure 2C). The AT1 expression pattern identified with the primary anti-AT1 antibody from Santa Cruz was identical to that detected in select sections with an alternative anti-AT1 antibody purchased from Sigma (data not shown).Figure 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)

Intracellular AT1 in neural and vascular cells of the adult human substantia nigra. AT1 is shown to be highly expressed in nigral dopamine neurons (A), in Iba1-positive microglia (B), and in S100B- (C) and GFAP-immunoreactive astrocytes (D-G) of a 69 years old prePD patient. AT1 is also detected in vascular smooth muscle cells in the tunica media (i.e., the medial layer) of the blood vessel wall (C). Scale bars are 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Intracellular AT1 in neural and vascular cells of the adult human substantia nigra. AT1 is shown to be highly expressed in nigral dopamine neurons (A), in Iba1-positive microglia (B), and in S100B- (C) and GFAP-immunoreactive astrocytes (D-G) of a 69 years old prePD patient. AT1 is also detected in vascular smooth muscle cells in the tunica media (i.e., the medial layer) of the blood vessel wall (C). Scale bars are 20 μm.
Mentions: In all patients examined, irrespective of their health status (AMC, prePD, or PD), we found AT1 in all dopamine neurons. Adding prominence to the brain’s AT1 expression profile is the fact that AT1 was also expressed in all neurons as evidenced by the AT1 immunoreactivity present in neurons that were immunopositive for a Pan Neuronal marker, but were not pigmented and/or immunopositive for TH. An example of such neuronal AT1 expression is illustrated in a nigral section from a 69-year old prePD patient (Figure 2A). In addition, in all patients examined, AT1 immunoreactivity was present in both Iba1-immunoreactive microglia (Figure 2B) and S100B- and GFAP-immunoreactive astrocytes (Figure 2C-G). AT1 expression was also noted in vascular smooth muscle cells of the blood vessels within substantia nigra (Figure 2C). The AT1 expression pattern identified with the primary anti-AT1 antibody from Santa Cruz was identical to that detected in select sections with an alternative anti-AT1 antibody purchased from Sigma (data not shown).Figure 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