Age Influences Microglial Activation After Cuprizone-Induced Demyelination

Abstract

Multiple sclerosis (MS) is a chronic inflammatory CNS disease, which causes demyelinated lesions and damages white and gray matter regions. Aging is a significant factor in the progression of MS, and microglia, the immune cells of the CNS tissue, play an important role in all disease stages. During aging, microglia are functionally altered. These age-related changes probably already begin early and might influence the progression of CNS pathologies. The aim of the present study was to investigate whether microglia in the middle-aged CNS already react differently to demyelination. For this purpose, several microglia markers (ionized calcium binding adaptor molecule 1 (Iba-1), P2RY12, F4/80, CD68, major histocompatibility complex II (MHCII), macrophage receptor with collagenous structure (Marco), Translocator protein 18 kD (TSPO), CD206, and CD163) were analyzed in the acute cuprizone demyelination model in young (2-month-old) and middle-aged (10-month-old) mice. In addition, microglial proliferation was quantified using double-labeling with proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU), which was injected with the onset of remyelination. To compare age-related microglial changes during de- and remyelination in both gray and white matter, the hilus of the dorsal hippocampal dentate gyrus (DG) and the splenium of the corpus callosum (CC) were analyzed in parallel. Age-related changes in microglia of healthy controls were more pronounced in the analyzed gray matter region (higher levels of F4/80 and Marco as well as lower expression of CD68 in middle-aged mice). During de- and remyelination, a stronger increase of the microglial markers Iba-1, CD68 and TSPO was observed in the splenium of the younger groups. There was a significant reduction of P2RY12 during demyelination, however, this was age- and region-dependent. The induction of the anti-inflammatory markers CD206 and CD163 was stronger in the middle-aged group, but also differed between the two analyzed regions. De- and remyelination led to a significant increase in PCNA+ microglia only in young groups within the white matter region. The number of BrdU+ microglia was not changed during de- or remyelination. These results clearly show that microglia are already altered during middle-age and also react differently to CNS demyelination, however, this is highly region-dependent.

Microglial motility in Alzheimer’s disease and after Aβ42 immunotherapy: a human post-mortem study

“…Thus, P2RY12 expression after immunotherapy might suggest an increase both in baseline and directed motility. This is also consistent with the neuroinflammatory environment observed in the immunised group, which is slightly leaning towards a more anti-inflammatory profile, considering evidence that P2RY12 is downregulated under pro-inflammatory conditions and upregulated in an anti-inflammatory context [22, 30]. Of note, a previous study by our group in the immunised group showed that neuronal loss is correlated with Iba1-positive microglia and phagocytic CD68-positive microglia associated with pro-apoptotic neurons, but without accelerated cognitive decline compared to non-immunised AD patients [36].…”

P2‐196: MICROGLIAL MOTILITY IN ALZHEIMER'S DISEASE AND AFTER Aβ42 IMMUNOTHERAPY: A HUMAN POSTMORTEM STUDY

“…Thus, P2RY12 expression after immunotherapy might suggest an increase both in baseline and directed motility. This is also consistent with the neuroinflammatory environment observed in the immunised group, which is slightly leaning towards a more anti-inflammatory profile, considering evidence that P2RY12 is downregulated under pro-inflammatory conditions and upregulated in an anti-inflammatory context [22,30].…”

Age‐dependent effect between MARCO and TLR4 on PMMA particle phagocytosis by macrophages

“…Additionally, we demonstrated that pMфs isolated from aged mice show elevated expression of MARCO receptor compared to the pMф isolated from young mice. Furthermore, our results are in accordance with the report showing the age‐dependently elevated expression of MARCO on the surface of microglia . On the other hand, it was shown that there is no difference in the level of MARCO expression between young and aged alveolar Mф .…”