Microglia, the brain’s immune cells, usually serve as diligent guardians. They eliminate intruders such as microbes and clear away cellular debris – including the plaques typical of Alzheimer’s disease. However, as our brains age, microglia also change. While some continue to function effectively, others gradually lose their protective role and start secreting small amounts of inflammatory cytokines. One such is interleukin-12 (IL-12). Through meticulous analyses, research teams led by Professor Frank Heppner, Director of the Department of Neuropathology at Charité – Universitätsmedizin Berlin, and Professor Nikolaus Rajewsky, Director of the Berlin Institute for Medical Systems Biology at the Max Delbrück Center (MDC-BIMSB), along with additional partners, have identified how IL-12 might trigger and accelerate Alzheimer’s dementia. Their study, published in Nature Aging, could pave the way for new combination therapies.
In 2012, Heppner’s lab reported in Nature Medicine that blocking IL-12 and IL-23 significantly reduced Alzheimer’s-related brain changes in mice. But they couldn’t unravel the underlying mechanism with standard techniques. Instead, scientists used single-cell analyses to reconstruct which genes are being read and translated into proteins in thousands of individual cells simultaneously. These analyses generate massive datasets, which can now be analyzed with the help of Artificial Intelligence and Machine Learning. However, a major challenge in using single cell sequencing technology is isolating individual cells from a tissue sample without damaging them or causing unintended changes. In aging mouse brains – especially those with Alzheimer’s plaques – cells are so stuck together and tangled that separating them cleanly is nearly impossible; this is why the process took years to be refined.
IL-12, previously known primarily for its role in autoimmune diseases like Crohn’s disease and rheumatoid arthritis, appears to play a pivotal role in Alzheimer’s progression. It damages two brain cell types: mature oligodendrocytes, which produce myelin (the fatty insulating layer around nerve fibers damaged in multiple sclerosis); and interneurons, which are particularly important for cognition and memory. IL-12 binding to interneurons causes them to die. A vicious circle begins: As more microglia produce IL-12, more brain cells sustain damage. Meanwhile, remaining functional microglia become overburdened by the task of clearing the additional cellular debris, and thus fail to remove Alzheimer’s plaques. To verify this mechanism, researchers tested it in mice and in human tissue. When Heppner’s team blocked IL-12 in cell cultures and mouse models, they could stem disease-related changes.
Electron micrographs of mouse brain tissue also showed how myelin structure and nerve fiber density changed depending on whether the IL-12 signaling pathway was present or absent. Mass spectrometric analyses (lipidomics) confirmed the altered composition of the fat-rich insulating layer. Study of autopsy tissue from Alzheimer’s patients provided further confirmation of the results – the more advanced the disease, the more IL-12 was present in the tissue. Cell cultures with human oligodendrocytes were also extremely sensitive to IL-12; this is why he study has immediate implications as there are already drugs on the market that block IL-12. Noteworthy, this contrasts with peripheral autoimmune diseases mediated through IL-12/IL-23 signaling, such as psoriasis or Crohn’s disease, where IL-23 has been identified as the main driver. The researchers hope that clinicians will build on their findings and initiate clinical trials.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialista in Biochimica Clinica.
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