29 November 2012. Just as turning down the gas lowers the heat in the kitchen, dialing back an inflammatory signaling pathway quenches amyloid-β in the brain, according to the November 25 Nature Medicine. Scientists led by Burkhard Becher, University of Zurich, Switzerland, and Frank Heppner, Charité–Universitätsmedizin Berlin, Germany, found that simultaneously mollifying two microglial cytokines—IL-12 and IL-23—prevents plaque buildup and improves behavior in mouse models of Alzheimer’s disease (AD). These same cytokines flare up in the cerebrospinal fluid of human AD patients, the authors report. The new study adds to mounting evidence that neuroinflammation fans AD pathology and suggests that blocking relevant cytokine pathways could slow disease development. Ustekinumab, an antibody to IL-12/23, already received FDA approval for the treatment of psoriasis, an autoimmune disease of the skin. The AD research comes hot on the heels of the news that mutations in the microglial receptor TREM2 triple AD risk (see ARF related news story).
Released by microglia, IL-12 and IL-23 stimulate maturation of naive T cells, which are part of the adaptive immune system. Each cytokine is made up of two subunits, with one, p40, being common to both. The other subunits, p35 and p19, are specific to IL-12 and IL-23, respectively. The two cytokines have been implicated in immune diseases such as psoriasis, multiple sclerosis, and Crohn’s, but scientists had not yet looked at their potential contribution to AD. A few hints have surfaced, however. A recent multi-analyte profiling study in MCI and AD patients reported that higher plasma p40 levels matched up with lower cognitive performance on the MMSE (see ARF related news story). What’s more, Aβ immunization in mice lowered T cell expression of IL-12RB1, a major component of receptors for both cytokines (see Town et al., 2002). But where is the common p40 subunit released? On which cells does it act? And does manipulating its level modulate AD pathology?
To answer those questions, joint first authors Johannes vom Berg and Stefan Prokop first compared microglia in wild-type older mice with microglia in APPPS1 transgenic mice, which develop early and aggressive cerebral amyloidosis. Not only were microglia in APPPS1 mice more activated, as others had found previously (see Frautschy et al., 1998), but they also produced more mRNA for p40, IL-12, and IL-23. When the researchers crossed APPPS1 mice with mice lacking p40, p35, or p19, cortical plaque load fell in four-month-old knockouts relative to APPPS1 controls. Mice without p40, and therefore without both IL-12 and IL-23, showed the most marked effect—a 63 percent decline. At eight months, APPPS1 p40 knockouts also had fewer microglia, their astrocytes were less aggravated, and their soluble and insoluble Aβ40 and 42 in the brain were half those in regular APPPS1 mice. Together, the results suggest that p40, and therefore IL-12 and IL-23, play a role in AD pathology, and that reining in those cytokines might suppress Aβ.
What cells make these cytokines? One major question in AD research is whether reactive glia reside in the brain or migrate in from the body’s peripheral blood circulation (see ARF related news story). To find out which pool of cells mediated the p40 effects, the researchers irradiated APPPS1 and APPPS1 p40 knockout mice to eliminate their peripheral macrophages (the skull protects brain cells from the radiation used in this experiment). They then replenished peripheral cells by injecting bone marrow from wild-type or p40 knockouts. With this approach, the scientists created mice with p40 restricted to either the central nervous system or the blood. The former accumulated plaque loads comparable to APPPS1 mice, while the latter generated far fewer plaques. “This told us that the p40 action takes place within the brain, not outside,” said Heppner.
“As far as I am aware, this is the first time that IL-12 and IL-23 have been implicated directly in an innate immune phenomenon,” said Richard Ransohoff of the Cleveland Clinic, Ohio, who was not involved with the work. He suggested it would be important next to characterize tau pathology in Heppner’s mice, since work by others suggests a tradeoff between stronger amyloid clearance and accelerated tau pathology (see Lee et al., 2010, and Bhaskar et al., 2010).
Could drugs mimic p40 knockout effects? Based on this study, it appears so. Compared to untreated mice, one-third fewer plaques developed in APPPS1 mice that got a twice-weekly injection of an anti-p40 antibody starting when they were four weeks of age, before the onset of plaques, and continuing until they were four months old. The same treatment helped older mice (six months old) with fully established Aβ pathology as well. A 60-day course of anti-p40 delivered directly to the brain rescued short-term memory deficits in the Barnes maze test and in a novel object recognition task. While plaque load did not budge in these older mice, soluble Aβ species in brain homogenates of these animals took a dive. The results hint that drugs targeting IL-12 and IL-23 could treat AD pathology and cognitive decline in humans, the scientists believe. In indirect support of this, Heppner and colleagues detected more p40 in the CSF of 39 AD patients compared to 20 controls. Furthermore, p40 levels correlated with worse cognitive performance on the MMSE.
IL-12 and IL-23 are two of many cytokines that control inflammatory and non-inflammatory signaling in glia. Researchers are only just beginning to understand how they all fit with AD pathology (see ARF related news story). While IL-12/23 may promote Aβ pathology in mice, other inflammatory cytokines, including IL-6 (see Chakrabarty et al., 2010) and interleukin 1β (Matousek et al., 2012), might help clear the peptide. On the other hand, blocking CD40 (see ARF related news story) or TGF-β (see ARF related news story) achieves a similar effect.
Vom Berg and colleagues add to mounting evidence that scientists will probably have to pick and choose which parts of the immune system to stimulate or suppress, said Terrence Town, Cedars-Sinai Medical Center, Los Angeles, California. "Pan-blocking inflammation is not going to be the way forward against AD. We have to focus on these very specific molecular cascades,” said Town. “This work demonstrates that blocking IL-12/IL-23 signaling could well be a critically important therapeutic target,” he added.
Heppner says his group plans to probe effects downstream of p40, while testing ustekinumab (see Weber and Keam, 2009), a human antibody to p40, in people at risk for AD. The antibody has been used to treat psoriasis since 2009, and “could be tested in a Phase 2 trial pretty quickly,” Heppner told Alzforum. Phase 3 trials are also underway to test its effectiveness against Crohn’s disease (see Sandborn et al., 2012), and a Phase 2 trial will examine whether ustekinumab can treat rheumatoid arthritis. The antibody did not pass primary endpoints in a Phase 2 trial for relapsing-remitting multiple sclerosis (see Segal et al., 2008).—Gwyneth Dickey Zakaib.
Vom Berg J, Prokop S, Miller KR, Obst J, Kälin RE, Lopategui-Cabezas I, Wegner A, Mair F, Schipke CG, Peters O, Winter Y, Becher B, Heppner FL. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease–like pathology and cognitive decline. Nature Medicine 2012 November 25. Abstract