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

Abstract

BackgroundIn 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.ResultsAT1 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.ConclusionsOur 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.

Alpha7 nicotinic receptor activation protects against oxidative stress via heme-oxygenase I induction

“…3C and D), which further corroborates the synergic effect of both stimuli. Since increases in Nox4 have been reported in NDDs [31][32][33], the fact that the LPS/AA combination in organotypic cultures also showed induction of Nox4, is another indication that this model reproduces neurodegenerative pathology.…”

Redox‐based therapeutics in neurodegenerative disease

“…Other recent developments in the PD/NOX field come from exploring the influence of angiotensin receptor activation on NOX‐derived ROS production. Following from rodent studies, in which dopamine loss and changes in NOX activity in the SN correlate with expression of the angiotensin AT 1 receptor, Zawada and colleagues measured the distribution of AT 1 receptors and NOX4 in different nigral compartments in post mortem samples from PD patients (Zawada et al ., ). The ratio of nuclear/total neuron AT 1 expression increased according to disease progression and was associated with increased levels of NOX4.…”

NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease

“…In the brain samples, nuclear AT1 was elevated, though the total AT1 decreased, with increasing disease severity. This accompanied an elevation in NOX4 and caspase-3, suggesting ANGII-activated NOX4 as a possible pathway of dopaminergic cell death in clinical PD (Zawada et al, 2015). Thus, NOX appears to play a key role in both PD development and progression and is a promising therapeutic target, both independently and via upstream signaling pathways such as ANGII.…”