Interleukin-10: the anti-inflammatory cytokine at the heart of the Alzheimer’s disease storm

One of the key pathological characteristics of Alzheimer’s disease is the build-up of extracellular amyloid plaques composed of A? peptides. Inflammation triggered by the innate immune system in response to these plaques has long been thought to promote the progression of Alzheimer’s disease, with the development of a ‘cytokine storm’ creating a self-reinforcing, neurotoxic feedback loop that promotes plaque deposition. Although various anti-inflammatory strategies have been proposed to tackle this problem they have met with little success.

Amyloid plaques

Pictured left: Amyloid plaques identified via immunohistochemical staining for A?42 are indicated by arrows on the left-hand side of the image. On the right-hand side of the image, where the plaques have been removed, A?42 is present in activated microglia (indicated by arrowheads) and is presumed to represent plaque A? that has been phagocytosed by the microglia. Abbreviation: A?, amyloid-?.

New research now challenges the cytokine storm hypothesis, offering hope that the immune system may be able to clear the A? plaques itself to reverse memory loss and cell damage. Two recent studies published in Neuron show that the anti-inflammatory cytokine interleukin-10 counterintuitively gave rise to detrimental effects in a mouse model of Alzheimer’s disease. IL-10 may contribute to, rather than reduce, the progression of Alzheimer’s disease by promoting A? plaque generation and exacerbating cognitive impairment.
Research from the University of Florida shows that the over-expression of anti-inflammatory IL-10 within the brain of an Alzheimer’s disease mouse model increased the levels of apolipoprotein E, a protein that facilitates the clearance of A? from the brain. The increased level of APOE observed with IL-10 expression, bound A? rather than clearing it from the brain and was itself sequestered within the plaques. This accelerated the build-up of plaque in the Alzheimer’s model.
Research from the University of South California used the alternative method, knocking out IL-10 expression within an Alzheimer’s disease background, to show that IL-10 deficiency promotes A? clearance. Alzheimer’s-afflicted mice lacking the anti-inflammatory cytokine, IL-10, behaved more like mice without the disease in various learning and memory tests. These results show that blocking IL-10 can not only prevent further damage to the brain, but also clear the brain of A? plaques, helping to restore the memory and improve cognitive ability.
The researchers at the University of South California now plan to test drugs that target IL-10 in a rat model of Alzheimer’s disease to examine the effectiveness of this cytokine as a target in the treatment of Alzheimer’s.
This unexpected finding that IL-10 does not act in its cemented anti-inflammatory role demonstrates the complex interplay between innate immunity and the turnover of protein in neurodegenerative disease and suggests that blocking IL-10 may be therapeutically relevant for Alzheimer’s disease.
With an increasing aging population, diseases such as Alzheimer’s may prove to be the public health crisis of our time, with a projected 16 million Americans over the age of 65 set to develop the disease by 2050. With no currently available real-time cures for Alzheimer’s disease, an increased understanding of the role of the innate immune system in this disease may open the door to future treatments.