Objective: To assess macrophages in the human brainstem in healthy ageing and during Parkinson’s disease (PD).

Background: PD is the second most common neurodegenerative disorder characterised by motor dysfunction. Dopamine (DA) loss, caused by neurodegeneration in the substantia nigra pars compacta (SNpc), underlies movement symptoms. Noradrenaline (NA) neurons in the locus coeruleus (LC) are also vulnerable in PD, whereas DA neurons in the ventral tegmental area (VTA) are relatively spared. In contrast to the VTA, SNpc and LC accumulate high levels of neuromelanin (NM). NM is released due to cell loss in PD, which causes cytokine release and microglial activation (Carballo-Carbajal et al., 2019; Laguna et al., 2024). There are other types of parenchymal and perivascular macrophages that undergo disease changes. It is suggested that border associated macrophages (BAMs) stimulate immune cell infiltration in the SNpc (Schonhoff et al., 2023).

Method: Formalin fixed paraffin embedded (FFPE) human brainstem sections were obtained from 8 controls, 5 preclinical, 10 early and 10 late PD cases from the Sydney Brain Bank with approval. Multiplex immunohistochemistry was performed, digital images acquired and anatomical regions annotated in the midbrain and pons. Different types of microglia and macrophages were identified and quantified in these regions.

Results: Microglia and BAMs, based on Iba1 and CD163 signal, were abundant in the LC, SNpc and VTA. Six macrophage types were observed, some of which have not been previously identified expressing both Iba1, CD163, and a proinflammatory cytokine. LC had the greatest variety of macrophage subtypes in healthy ageing. In contrast, SNpc and VTA had only three main types. We found a significant region effect on macrophage density in controls [F (2, 69) = 11.51, p<0.0001] and across PD stages [F (3, 69) = 4.331, p=0.0074], with macrophage subtypes changing across regions in PD. For example, the LC showed a significant reduction of the pro-inflammatory BAM subtype in late PD (Tukey’s post-hoc test, p=0.0225).

Conclusion: There are significant differences in the amount and type of macrophages in the human pigmented cell regions in healthy ageing. In PD there is an overall difference in macrophage density, however there is a specific reduction of proinflammatory BAMs in the LC. This suggests that peripheral immune cell recruitment may differ regionally in PD.

References: Carballo-Carbajal, I., Laguna, A., Romero-Giménez, J., Cuadros, T., Bové, J., Martinez-Vicente, M., Parent, A., Gonzalez-Sepulveda, M., Peñuelas, N., Torra, A., Rodríguez-Galván, B., Ballabio, A., Hasegawa, T., Bortolozzi, A., Gelpi, E., & Vila, M. (2019). Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis. Nat Commun, 10(1), 973. https://doi.org/10.1038/s41467-019-08858-y

Laguna, A., Peñuelas, N., Gonzalez-Sepulveda, M., Nicolau, A., Arthaud, S., Guillard-Sirieix, C., Lorente-Picón, M., Compte, J., Miquel-Rio, L., Xicoy, H., Liu, J., Parent, A., Cuadros, T., Romero-Giménez, J., Pujol, G., Giménez-Llort, L., Fort, P., Bortolozzi, A., Carballo-Carbajal, I., & Vila, M. (2024). Modelling human neuronal catecholaminergic pigmentation in rodents recapitulates age-related neurodegenerative deficits. Nature Communications, 15(1), 8819. https://doi.org/10.1038/s41467-024-53168-7

Schonhoff, A. M., Figge, D. A., Williams, G. P., Jurkuvenaite, A., Gallups, N. J., Childers, G. M., Webster, J. M., Standaert, D. G., Goldman, J. E., & Harms, A. S. (2023). Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease. Nature Communications, 14(1), 3754. https://doi.org/10.1038/s41467-023-39060-w

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MDS Abstracts - https://www.mdsabstracts.org/abstract/macrophage-subtypes-in-brainstem-catecholamine-regions-in-healthy-ageing-and-across-parkinsons-disease/