A recent study, published in Nature Medicine is perhaps the first one to suggest a putative interleukin (IL)-23 involvement in Alzheimer’s disease, and that blocking IL-12 and IL-23 shows promise as an experimental therapeutic approach.
Despite some descriptive evidence for differential expression of inflammatory mediators in Alzheimer’s disease, studies on the expression patterns of proinflammatory cytokines are sparse. Glial cells, especially microglia, which typically associate closely with Aβplaques, are reported to be a major source of proinflammatory cytokines in many CNS diseases, including Alzheimer’s diseaseand its corresponding mouse models.
IL12 and IL23 share a common subunit (p40), as well as thesignaling chain of their respective receptors (IL12Rβ1). Although the number of different leukocyte cell types that are known to be able to respond to IL12 and IL23 is growing, the role of IL12/IL23 signaling in the context of amyloidinduced neurodegeneration has not yet been established.
In the Nature Medicine study Johannes vom Berg and colleagues, as part of a joint Swiss and German research team, found that the microglial cells in the brains of the mouse model of Alzheimer’s disease expressed high levels of IL-12 and IL-23, including during the formation of amyloid plaques.
As IL-12 and IL-23 share a common subunit (p40), blocking p40 signaling in APPPS1 mice by peripheral (intraperitoneal), or central (intracerebroventricular) injection with the neutralizing p40-specific antibody reduced amyloid beta deposits in the brain and improved cognitive deficits in aged APPPS1 mice.
Notably, checking the translational significance in humans, the authors found that the concentrations of p40 were increased in the cerebrospinal fluid of Alzheimer’s disease patients, and individuals with higher levels of p40 had lower cognitive performance.
The authors discuss that the IL-12 and IL-23 signaling might be “crucially involved in regulating not only the amount of a central component of Alzheimer’s disease pathology, namely, Aβ plaques, but also cognitive impairment”.
As p40-neutralizing antibodies and the IL-12/23inhibitors (ustekinumab) are approved in the United States, Canada and Europe to treat moderate to severe plaque psoriasis, the authors also suggest that treatment trials in subjects with mild cognitive impairment or Alzheimer’sdisease may be warranted.
More recent research seems to substantiate and support the 2012 vom Berg’s study showing increased serum levels of IL-23, and the presence of IL-12A, IL-12B and IL-23R polymorphisms in patients with Alzheimer’s disease.
Besides neurodegeneration, the disease-accelerating role of neuroinflammation has become a focus of research in AD. Also, the central role of IL-23 in neuroinflammation, especially in multiple sclerosis (MS), and the role of IL-23 in the development of MS is now well established. Thus, IL-23 is increased in serum, cerebrospinal fluid (CSF), and lesional tissue of MS patients.
AD patients show higher peripheral levels of IL-23. Thus, serum concentrations of IL-23, IL-17 and IL-18, are significantly higher in AD patients than controls. Of note, the serum level of IL-23 was observed to be significantly higher in female AD patients than male AD patients.
Cover Image Credit (Left Panel): Interleukin (IL)-12 and IL-23 structure and receptors. Notes: The IL-12 cytokine is composed of two chains, p35 and p40, which are covalently linked. p40 is shared by IL-23, which has another subunit, p19. The IL-12 receptor consists of IL-12Rβ1 and IL-12Rβ2, while the IL-23 receptor results from the association of IL-12Rβ1 and IL-23R. Ustekinumab is a human monoclonal antibody that binds to p40 shared by IL-12 and IL-23. Ustekinumab blocks the interaction of IL-12 and IL-23 with their receptor. From: Ustekinumab in chronic immune-mediated diseases: a review of long term safety and patient improvement, by Eric Toussirot et al., Patient Prefer Adherence, 2013 Apr 26;7:369-77n .