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Circadian Control of Immune Cell Linked to Clearance of Alzheimer’s Protein

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A new study has discovered that the brain’s ability to clear the protein amyloid-β 42 (Aβ42) – which plays a key role in Alzheimer’s disease pathogenesis – is linked to our circadian rhythms. The results are published in PLoS Genetics.

Circadian rhythms and Alzheimer’s disease

A growing body of research continues to demonstrate associations between disrupted circadian rhythms and diseases. Alterations in circadian rhythms – such as the sleep-wake rhythm – are prominent in a variety of neurodegenerative diseases, like Parkinson’s disease, Huntington’s disease and Alzheimer’s disease.

What are circadian rhythms?  

Circadian rhythms are endogenous clocks – meaning they originate within the body – that cause oscillations in levels of proteins, such as enzymes and hormones. Circadian rhythms control the rhythmic expression of a large majority of the genome, which is transcribed and translated into proteins that are implicated in biological processes. Such oscillations might lead to changes in body temperature, appetite, drowsiness and immune response.

A clinical hallmark of Alzheimer’s disease is the formation of Aβ42 plaques that disrupt neuronal function. These plaques are cleared by a type of immune cell found in the brain called microglia (in the periphery, these immune cells are known as macrophages) via phagocytosis. Macrophages and microglia are an example of myeloid cells.

Dr. Jennifer Hurley, associate professor of biological science at Rensselaer Polytechnic Institute, focuses on the molecular mechanisms underlying circadian rhythms in her research. Previously, Dr. Hurley and colleagues at the Royal College of Surgeons in Ireland identified which macrophage RNAs – and corresponding proteins – oscillate with a circadian rhythm. 

“We know that there is a daily oscillation in the levels of Amyloid beta in the brain,” she told Technology Networks. “We also know that microglia, the macrophages of the brain, are responsible for clearing the Amyloid beta.”

“Our previous research had told us that there was a circadian oscillation in the phagocytosis of particles in mammalian macrophages. We thought perhaps there is a link between the two, and that there is an oscillation in the phagocytosis of Amyloid beta.”

This was indeed the case – Hurley and colleagues found that Amyloid beta phagocytosis did oscillate with a circadian period. But, which pathways underlie this regulation?

“We tested pathways known to regulate phagocytosis and found these pathways did not control the rhythm. A collaborator on this work suggested that heparan sulfate – found on the cell surface – could be involved. It regulates Amyloid beta fibril formation,” Hurley said. “This led us to track the levels of heparan sulfate over circadian time.”

What is heparan sulfate?

Heparan sulfate is a proteoglycan found on the cell surface and in the extracellular matrix. It is known to interact with a myriad of different ligands and these interactions have gained increasing research attention over recent years.

An elegant study

The research team relied on two key techniques for this work. “First, we employed a model of phagocytosis that we had developed for earlier work where we derive macrophages from bone marrow (thus avoiding pitfalls associated with cell lines) to track phagocytosis over time,” Hurley said. “Second, we collaborated with an expert in the analysis of heparan sulfate, who was able to use mass spectrometry (MS) to give us a full profile of heparan sulfate levels in the macrophages over time,” she added.

Evidence of a relationship between circadian rhythms, proteoglycans and Aβ42 clearance

The researchers found that, in macrophages, cell surface proteoglycan production was at its lowest level when clearance of Aβ42 was at its highest: “LC-MS/MS analysis of macrophages over circadian time showed a distinct rhythm in heparan sulfate proteoglycan levels,” the authors write in the publication.

When the macrophages were treated with enzymes that break down heparan sulfate proteoglycans, the oscillation of Aβ42 phagocytosis was disrupted and increased phagocytosis occurred.

“Overall, our data suggests a role for myeloid cells in the circadian timing of the clearance of Aβ42 and an avenue through which the disruption of circadian rhythms can lead to enhanced AD pathogenesis,” the authors write in the publication. Hurley emphasized that the research team are not sure why this regulation occurs, but that it demonstrates that a relationship exists between the circadian clock, proteoglycans and clearance of Aβ42.

Hurley emphasized that there are always limitations with scientific research studies, and in this case, it’s the ex vivo nature of the work using macrophages, not microglia. “Though these macrophages often behave as microglia do, there could be differences in behaviour between the naïve and brain resident macrophages,” she said.

Potential impact on the treatment of Alzheimer’s disease

The treatment landscape for Alzheimer’s disease has – unfortunately – progressed slowly over recent decades. Many therapeutics that target Amyloid beta clearance have failed in clinical trials. Technology Networks asked Hurley how this study might have an impact on Alzheimer’s disease treatment strategies.

“The reason for the failure of Amyloid beta clearance is not well understood, but it has been suggested that by the time that we apply treatment, the damage may have already been done by excess Amyloid beta or that the treatments are not effectively clearing Amyloid beta,” she said. “The great thing about this study is it suggests a mechanism that may work beyond the clearance of Amyloid beta to other fibril-forming proteins.”

Hurley emphasized that this work also provides a potential mechanism to explain why simple life changes, such as good circadian hygiene – both early and late in life – could ease Alzheimer's symptoms or perhaps prevent the development or progression of disease without the need for medications.

Heparan sulfate is also widely involved in the inflammatory response, meaning its oscillation on the cell surface could have potential implications for other aspects of human health and disease.

The next steps for Hurley and colleagues will be to understand how the regulation occurs, in the hope that they can find a way to control it therapeutically. “We are also investigating the effect that disrupting the circadian clock has on developing Alzheimer’s disease,” she said. “Finally, we are working on what the other health implications of heparan sulfate oscillations may be.”

Dr. Jennifer Hurley was speaking to Molly Campbell, Senior Science Writer for Technology Networks.

Reference: Clark G, Yu Y, Urban C et al. Circadian control of heparan sulfate levels times phagocytosis of Amyloid beta aggregates. PLoS Genetics. doi: 10.1371/journal.pgen.1009994.