Complement activation in the Parkinson's disease substantia nigra: an immunocytochemical study - PubMed (original) (raw)

Complement activation in the Parkinson's disease substantia nigra: an immunocytochemical study

David A Loeffler et al. J Neuroinflammation. 2006.

Abstract

Background: Inflammatory processes are increased in the Parkinson's disease (PD) brain. The long-term use of nonsteroidal anti-inflammatory drugs has been associated, in retrospective studies, with decreased risk for PD, suggesting that inflammation may contribute to development of this disorder. The objective of this study was to determine the extent of complement activation, a major inflammatory mechanism, in PD.

Methods: Substantia nigra specimens from young normal subjects (n = 11-13), aged normal subjects (n = 24-28), and subjects with PD (n = 19-20), Alzheimer's disease (AD; n = 12-13), and dementia with Lewy bodies (DLB; n = 9) were stained for iC3b and C9, representing early- and late-stage complement activation, respectively. Numbers of iC3b+, C9+, and total melanized neurons in each section were counted in a blinded fashion. Nonparametric analyses were used to evaluate differences between groups and to evaluate correlations between complement staining, numbers of melanized neurons, and the duration of PD.

Results: Lewy bodies in both PD and DLB specimens stained for iC3b and C9. Staining was also prominent on melanized neurons. The percentage of iC3b+ neurons was significantly increased in PD vs. aged normal and AD specimens, and in young normal vs. aged normal specimens. C9 immunoreactivity was significantly increased in PD vs. AD specimens, but unlike iC3b, the increased C9 staining in PD and young normal specimens did not achieve statistical significance vs. aged normal specimens. iC3b and C9 staining in PD specimens was not correlated with the numbers of remaining melanized neurons, nor with the duration of PD.

Conclusion: Complement activation occurs on Lewy bodies and melanized neurons in the PD substantia nigra. Early complement activation (iC3b) is increased on melanized neurons in PD vs. aged normal specimens, and late-stage complement activation (C9) also tends to increase. This latter finding suggests that complement activation may contribute to loss of dopaminergic neurons in some individuals with PD. Complement activation on melanized neurons appears to decrease with normal aging, suggesting a possible neuroprotective role for this process in the normal substantia nigra.

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Figures

Figure 1

Figure 1

iC3b staining in substantia nigra specimens. Fig. 1A: Immunoreactive Lewy bodies in a PD substantia nigra specimen; Fig. 1B: Staining of melanized neurons (arrows) in a different PD specimen; Fig. 1C: Immunoreactive neuron with little melanin remaining, same PD specimen as Fig. 1B; Fig. 1D: iC3b staining of melanized neurons (arrows) in a young normal specimen; compare with unstained neurons in lower part of field; Fig. 1E: similar staining pattern in an AD specimen; two prominently stained melanized neurons are seen (arrows) among several unstained neurons; Fig. 1F: iC3b-stained senile plaques in a different AD substantia nigra specimen. (Figs. 1A and 1C, bar = 10 μm; Figs. 1B and 1D–F, bar = 50 μm; immunoreactive structures are dark blue or gray, in contrast to brown melanin and yellow background).

Figure 2

Figure 2

C9 staining in substantia nigra specimens. Fig. 2A: Staining of multiple Lewy bodies within a melanized neuron in a PD specimen; adjacent melanized neuron (arrow) and its axon are also C9-positive; Fig. 2B: immunoreactivity for C9 in a Lewy body (arrowhead) and in melanin-depleted neurons (arrows) in a different PD specimen; Fig. 2C: staining of melanized neuron (arrow) and its processes in a DLB specimen; Fig 2D: multiple immunoreactive melanized neurons in an aged normal specimen. (Fig. 2A, bar = 10 μm; Figs. 2B–D, bar = 50 μm; immunoreactive structures are dark blue or gray, in contrast to brown melanin and yellow background).

Figure 3

Figure 3

Percentages of iC3b-positive melanized neurons in different groups of substantia nigra specimens. The percentage of iC3b+ melanized neurons was significantly increased in PD vs. both aged normal and AD specimens, and in young normal vs. aged normal specimens. Data are expressed as means ± SEM. (a_p_ < 0.05 vs. PD; b_p_ < 0.05 vs. young normal specimens; abbreviations: AD, Alzheimer's disease; AN, aged normal; DLB, dementia with Lewy bodies; PD, Parkinson's disease; YN, young normal)

Figure 4

Figure 4

Numbers of melanized neurons in different groups of substantia nigra specimens. Total numbers of melanized neurons were significantly decreased in PD vs. aged normal, young normal, and AD specimens, and in DLB vs. aged normal and AD specimens. Data (means ± SEM) are shown for slides from specimens in which iC3b immunoreactivity was assessed; essentially similar results were obtained for slides from specimens in which C9 staining was evaluated. (a_p_ < 0.05 vs. PD; b_p_ < 0.05 vs. DLB; abbreviations: AD, Alzheimer's disease; AN, aged normal; DLB, dementia with Lewy bodies; PD, Parkinson's disease; YN, young normal)

Figure 5

Figure 5

Percentages of C9-positive melanized neurons in different groups of substantia nigra specimens. C9 staining was significantly increased in PD vs. AD specimens. The percentages of C9+ melanized neurons in PD and young normal specimens tended to be increased vs. aged normal specimens, but these differences were not significant (p = 0.04 [not significant after adjustment for multiple comparisons] and 0.08, respectively). Data are expressed as means ± SEM. (a_p_ < 0.05 vs. PD; abbreviations: AD, Alzheimer's disease; AN, aged normal; DLB, dementia with Lewy bodies; PD, Parkinson's disease; YN, young normal)

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