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.
Alzheimer’s disease (AD) is the most common type of dementia in the elderly population, and its prevalence is increasing with the rapidly growing global elderly population. AD is characterized by progressive memory loss and other cognitive dysfunctions, such as impaired locomotor ability, reasoning, and judgment.
Studies of transgenic mouse models of AD suggest the impairment of microglial function to reduce Aβ burden as a causal factor in the disease. Chronic neuroinflammation induced by microglia contributes to pathological progression and symptom severity in late stages of the disease.
Interleukin-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. Interleukin-33, an alarmin of the IL-1 family, is also a crucial mediator of the innate immune response and a regulator of immune cell infiltration and activation.
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.