Nadine Rouleaux

During my final research internship at the Philip Haydon lab at Tufts University, Boston, USA I performed a research project in the field of my greatest interest, Alzheimer’s disease (AD).

This challenging project focused on unraveling the clearance process of amyloid beta (Aβ) from the brain to the cerebrospinal fluid (CSF), to increase our understanding of the complex disease mechanisms underlying AD. More specifically, we aimed to examine the role of P2Y6 receptors in the clearance of Aβ using antagonists and agonists for this receptor, as this receptor comprised the ‘life work’ of Prof. Philip Haydon.

To make a long story short, our results showed that stimulating the P2Y6 receptor increases the clearance of Aβ42 from the brain into the CSF. Presumably, it was suggested that the positive effects on Aβ42 clearance were due to increased phagocytosis of the neurotoxic protein as a result of P2Y6 receptor activation on microglia. However, I was not fully convinced that microglial phagocytosis could be solely responsible for the clearance of Aβ42 from the brain to the CSF. Thus, I have been thinking about what could lead us to these results, whether something strange happened during the experiments? Yes, indeed, I did notice something that all of a sudden got my full attention. During the collection of CSF (in mice) I noticed a pulsation of the CSF in the brain. And although I cannot be sure that this might be an artifact due to the brain surgery, my gut feeling told me this would be a very important observation.

Lately, there has been quite some discussion on the different clearance mechanisms for the clearance of Aβ from the brain. One of the mechanisms suggested are the perivascular and/or glymphatic pathways, which comprises the para-arterial influx of CSF into the brain through penetrating cerebral arteries, and the paravenous efflux of interstitial fluid (ISF) along large draining veins to the bloodstream, the lymphatic system or back to the CSF compartment. The key is, this specified clearance system CSF/ISF bulk flow is – probably – driven by the pulsation of these large penetrating cerebral arteries. However, how does this relate to my research on the P2Y6 receptor and the clearance of Aβ? In addition to microglia, the P2Y6 receptor is also located on vascular smooth muscle cells and endothelial cells, which play an important role in mediating the contraction (and thereby the pulsation) of cerebral arteries.

Thus, stimulating the P2Y6 receptor on vascular smooth muscle cells mediates cerebral arterial contractions, thereby modulating cerebral arterial pulsation. These changes in pulsatility could lead to increased CSF bulk flow through the brain, resulting in increased clearance of soluble Aβ from brain to CSF. In addition, activation of P2Y6 receptors on microglia stimulates microglial phagocytosis, probably resulting in the degradation of insoluble plaques into more soluble forms of Aβ, which the brain is able to clear through CSF-ISF clearance pathways. However, these P2Y6 receptor-mediated clearance mechanisms may become impaired during aging and AD as a result of, for instance, vascular aging, atherosclerosis and micro- bleeds. Moreover, in an inflammatory environment, P2Y6 receptors located on endothelial cells might even facilitate the inflammatory process, thereby further reducing the clearance capabilities of the brain.

Although these findings may create the basis for a potential new concept for the clearance of Aβ, many questions remain and further research is required. Nevertheless, it is my main goal to share my thoughts and ideas with professionals in the field of Alzheimer’s disease research, and to know their professional opinion on this matter. In the end, I think it holds great potential and it would be amazing to further unravel the clearance mechanism of Aβ from the brain to the CSF.