Interleukin-33 Reverses Cognitive Deficits in Alzheimer’s Mouse Model Showing Promise as a Therapeutic Target
A new study published in the Proceedings of the National Academy of Sciences USA (PNAS) indicates that interleukin-33 (IL-33) is able to improve memory deficits and reduce the accumulation of β-amyloid in APP/PS1 mice that exhibit Alzheimer’s disease (AD)-like pathologies.
IL-33 is a member of the IL-1 cytokine family and is considered an ‘alarm’ molecule due to its release after necrosis or tissue damage.
IL-33 is a potent driver of T helper type 2 (Th2) polarization, but recent evidence indicates that type 2 innate lymphoid cells (ILC2s) are perhaps the main target of IL-33. At the site of inﬂammation, IL-33 induces mainly IL-5 and IL-13 release by ILC2s, resulting in eosinophil recruitment, maturation of DCs, and activation of macrophages.
IL-33 has been implicated in allergy, mostly via the up-regulation of mast cell-derived IL-13, and in psoriasis, via the interactions between IL-33, substance P (SP) and mast cells. IL-33 also contributes to obesity, intestinal inﬂammation, and tumorigenesis.
An increasing body of evidence indicates that the innate immunity is a major player in AD development. For example, in the same APP/PS1 AD disease mouse model, as mentioned above, an increased production of IL-12 and the IL-23 subunit p40 by microglia was recently reported. Importantly, blocking the IL-12/IL-23 pathway by neutralizing antibodies was able to reduce AD-related pathology and cognitive deficits. Previous research also indicates that IL-33 expression is decreased in the brain of patients with AD, and that IL-33 expression is confined to the vascular capillaries in the brain.
In the PNAS study, Amy K. Y. Fu and colleagues from the Hong Kong University of Science and Technology, China, and the University of Glasgow, UK demonstrate that IL-33, administered in APP/PS1 mice that develop progressive AD-like disease with ageing is able to reverses synaptic plasticity impairment and memory deficits. The authors provide evidence that this effect was mainly due to an increased microglial phagocytosis and degradation of Aβ.
The finding that IL-33 specifically enhances Aβ uptake by microglia is of a particular interest as the clearance of Aβ is considered to be a major disease culprit in AD. As discussed by the authors, the increased numbers of CD68+ phagocytic microglial cells in close vicinity of amyloid plaques in APP/PS1 mice strongly indicates that IL-33 is able to restore the phagolysosomal activity, promoting Aβ clearance.
Additionally, the authors have shown that IL-33 directs the microglia/macrophages to an alternative activation phenotype, resulting in a reduction of the pro-inflammatory response in the AD mouse brains.
The authors speculate that in healthy individuals, high brain levels of IL-33 may play a protective role, while the deficit of IL-33 may contribute to AD in individuals that develop this disease.
The study provides news insights into the pathogenesis of AD and may indicate novel target and approach and/or a potential breakthrough in the treatment of AD. According to the University of Glasgow newsroom, the researchers are entering Phase I clinical trial to test the toxicity of IL-33.