Deposition of insoluble aggregates of amyloid β (Aβ) are hallmarks of Alzheimer’s disease (AD) [1]. Since microglia, the immune cells of the brain, help clearance of amyloid aggregates, disruption of microglial function is thought to be a key mechanism in AD neuropathology [2]. This has led to a search for soluble factors that could modulate microglial-mediated clearance of Aβ [3], [4]. A recent study by Jiang et al [5] identified soluble ST2 (sST2) as one such factor; notably, blood and brain levels of sST2 are elevated during aging. ST2 is a decoy receptor of interleukin 33-ST2-signaling that is secreted by endothelial cells and readily crosses the blood–brain barrier. The authors show that elevated sST2 levels block microglial activation by binding to, and reducing, cytokine interleukin-33 levels, a process that leads to decreased clearance of Aβ.
Jiang and colleagues went on to demonstrate that even aged persons with a genetic variant of ST2 (rs1921622) express lower levels of sST2 in the blood and brain and are less likely to develop AD. Further, they found that carrying the IL1RL1 rs1921622 polymorphism significantly lowers the chance of women carrying the APOε4 gene – the strongest genetic risk factor for AD – to develop the disease. These findings were backed by postmortem results showing that carriers of “protective” IL1RL1 rs1921622 had lower Aβ plaque loads. The authors ascribe this to better microglial clearance of Aβ in IL1RL1 rs1921622 carriers (See Fig. 1).
Fig. 1.
Endothelial soluble factor sST2 levels increase during aging and can easily cross the BBB to reach the brain (left panel). sST2 binds to IL-33 and blocks the activation of microglial cells and removal of Aβ aggregates and leading to its accumulation in the brain. People with the IL1RL1 rs1921622 polymorphism have less sST2; accordingly, it is suggested that the reduced blockage of IL-33 and subsequent microglial activation by IL-33 to increase the phagocytosis of Aβ aggregates (right panel).
How exactly IL1RL1 rs1921622 lowers sST2 levels remains unclear, but initial investigations showed that the rs1921622-containing region is an enhancer element that can regulate the ST2.
This new work suggests that lowering sST2 levels could be useful in preventing AD in at-risk subjects and possibly, in hampering further Aβ deposition in AD patients. In this respect, it is worth noting that at least two studies [6], [7] show that combined sacubitril/valsartan treatment for heart failure reduces peripheral sST2 levels. This combinatorial therapy also seems effective in the management of hypertension [8], a risk factor for neurodegeneration and dementia [9].
Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Sadashiva Pai is a founder and CEO of Science Mission LLC.
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