CD163 may account for Parkinson’s sex differences in mice

Protein may regulate how immune cells react to alpha-synuclein aggregation

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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The protein CD163, which is involved in the immune response, may play a protective role in Parkinson’s, particularly in females, by regulating how immune cells react to the toxic clumps of alpha-synuclein protein that lead to the disease’s symptoms, a study in mice finds.

The study, led by Marina Romero-Ramos, PhD, an associate professor at Aarhus University, Denmark, may unlock important insights into why more men than women develop and are diagnosed with Parkinson’s.

“We believe that the sex differences observed in the risk to develop [Parkinson’s], higher in males, as well as the disparities in the disease presentation between sexes might be due to differences in the immune response,” Romero-Ramos said in a press release. 

The study, “Sex-dimorphic neuroprotective effect of CD163 in an [alpha]-synuclein mouse model of Parkinson’s disease,” was published in NPJ Parkinson’s Disease.

Parkinson’s is about twice as common in men as women, yet tends to progress more rapidly in women. Why this happens is unclear, but some evidence suggests the immune response may take different forms in men versus women with Parkinson’s.

“However, little is known about what proteins might be involved in the differential immune response and/or which ones might exert a neuroprotective effect,” the researchers wrote.

CD163 is elevated in the blood of women with late-stage Parkinson’s, but not men, and its presence on more myeloid cells, which can develop into different types of blood cells, is linked to less inflammation in the brain, suggesting it is neuroprotective.

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Knocking out CD163 to better understand its function

To better understand the role of CD163, the researchers used a mouse model in which the gene that codes for the protein had been turned off or “knocked out.” This means that, unlike wild-type, or healthy, mice, knockout mice weren’t able to produce CD163.

Parkinson’s symptoms were induced by injecting preformed fibrils of alpha-synuclein, which are small protein clumps that can grow into Lewy bodies that are toxic to nerve cells and shape how the disease develops and progresses over time.

As expected, mice given the preformed fibrils took more steps and made more errors per step when crossing a beam with gradually narrowing sections than untreated mice, indicating motor symptoms.

A month after the injection, male knockout mice made more errors than wild-type mice when crossing the beam from wide to narrow, but the female mice didn’t. At six months, this difference persisted in males and all the female mice took longer to complete the task, indicating worsening motor function over time.

When placed in a hollow glass cylinder to check for spontaneous movements, male knockout mice didn’t use their hind limbs as much as wild-type mice a month after the injection. Female knockout mice walked more steps than the males.

While at six months there were no differences in how much paws were used, male knockout mice used one side significantly more than the other, but not females. Overall, alpha-synuclein led “to motor alterations that appeared distinct and sex-dependent in CD163-deficient mice, but not in [wild-type] mice,” the researchers wrote.

Buildup of alpha-synuclein

At that point, alpha-synuclein was seen to build up across a number of regions in the brain at significantly higher levels in knock-out versus wild-type mice and more so in the female than male mice. Without CD163, the brain appeared not to be able to prevent the toxic clumps from building up.

When the researchers looked for differences in the number of myeloid cells with phagocytic activity, that is, those that surround and clear unwanted or harmful substances, they found more of the cells in the brain of mice injected with the preformed fibrils than in the untreated mice.

This increase was more pronounced in male knockout mice after a month. In knockout mice, myeloid cells were also larger, suggesting greater phagocytic activity. After six months, however, female knockout mice showed a high number of microglia, the brain’s resident immune cells.

“Our observations suggest that CD163 promotes [an] early myeloid phagocytic response to [alpha-synuclein],” the researchers wrote. “Its absence in females results in … microglia proliferation in [the] long term.” Recent work has shown that microglia can be neuroprotective in the early stages of Parkinson’s, but contribute to inflammation as the disease progresses.

When alpha-synuclein builds up in the brain, it activates T-cells, an immune cell involved in mounting a more specific immune response. A month after preformed fibrils were injected, T-cell infiltration was seen in male, but not female, knockout mice. T-cell infiltration did occurr later in females.

“Our study suggests that CD163 is involved in the mechanism controlling the entrance of lymphocytes in the brain during neurodegeneration,” Romero-Ramos said.

Without CD163, male Parkinson’s mice showed early and ongoing motor symptoms, whereas female mice had a different response. Initially, their immune response was weaker, but it intensified after six months, leading to more severe brain damage.

It’s possible that increased CD163 occurs in Parkinson’s as a “compensatory neuroprotective mechanism,” the researchers wrote, and that female patients see more rapid neurodegeneration due to an altered immune response.

“Future studies may provide further molecular insights into the role of CD163 in brain diseases, and the mechanisms underpinning” any sex differences, the researchers said.