Blocking IL-12 and IL-23 in APPPS1 Mouse Model Shows Promise as an Experimental Therapeutic Approach to Alzheimer’s Disease

Blocking IL-12 and IL-23 in APPPS1 Mouse Model Shows Promise as an Experimental Therapeutic Approach to Alzheimer’s Disease

A recent study, published in Nature Medicine is perhaps the first one to show interleukin (IL)-23 involvement, and implicates both IL-23 and IL-12, key pro-inflammatory cytokines in the pathogenesis of Alzheimer’s disease.

Importantly, it also demonstrates that in the APPPS1 Alzheimer’s disease mouse model, preventing the effects of these mediators, or ‘immune hormones’, with antibodies against a common component of these proteins, could reduce the formation of amyloid beta (Ab) plaque.

In this 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’s disease 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.

Source: Nat Med, 2012, 12:1812-9. doi: 10.1038/nm.2965. Epub 2012 Nov 25.
Read more: nature.com
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