IL-33 Clears Amyloid and Reverses Symptoms in a Mouse Model of Alzheimer's Disease

Researchers here demonstrate a method of spurring microglia to attack amyloid in mice. It should be said that this is only the latest in a number of approaches shown to clear amyloid and improve symptoms in a mouse model of Alzheimer's disease. Alzheimer's research is an area in which a great many research results fail on moving from mice to people, but that said, there is a lot of independent evidence for microglia to be a useful target in Alzheimer's and other neurodegenerative conditions.

A study has discovered that a protein called IL-33 can reverse Alzheimer's disease-like pathology and cognitive decline in mice. "Alzheimer's disease currently has an urgent unmet clinical need. We hope that our findings can eventually be translated into humans. IL-33 is a protein produced by various cell types in the body and is particularly abundant in the central nervous system (brain and spinal cord). We carried out experiments in a strain of mouse (APP/PS1) which develop progressive AD-like disease with ageing. We found that injection of IL-33 into aged APP/PS1 mice rapidly improved their memory and cognitive function to that of the age-matched normal mice within a week."

The hallmarks of Alzheimer's include the presence of extracellular amyloid plaque deposits and the formation of neurofibrillary tangles in the brain. During the course of the disease, 'plaques' and 'tangles' build up, leading to the loss of connections between nerve cells, and eventually to nerve cell death and loss of brain tissue.‌ IL-33 appears to work by mobilising microglia (immune cells in the brain) to surround the amyloid plagues, take them up and digest them and reduces the number and size of the plaques. IL-33 does so by inducing an enzyme called neprilysin, which is known to degrade soluble amyloid. In addition, the IL-33 treatment worked by inhibiting the inflammation in the brain tissue, which has been shown earlier to potentiate plaque and tangle formation. Therefore IL-33 not only helps to clear the amyloid plague already formed but also prevent the deposition of the plaques and tangles in the first place.‌‌

"The relevance of this finding to human Alzheimer's is at present unclear. But there are encouraging hints. For example, previous genetic studies have shown an association between IL-33 mutations and Alzheimer's disease in European and Chinese populations. Furthermore, the brain of patients with Alzheimer's disease contains less IL-33 than the brain from non-Alzheimer's patients. Exciting as it is, there is some distance between laboratory findings and clinical applications. We are just about entering Phase I clinical trial to test the toxicity of IL-33 at the doses used. Nevertheless, this is a good start."



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