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. Nat Med. 2012 Dec;18(12):1812-9. PubMed.
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Klinik und Poliklinik für Neurologie
Microglial Cytokines Light the Fire—Interleukin 12-, Interleukin 23-Mediated Inflammation May Act as Driving Force Behind Disease Progression
The paper by vom Berg and colleagues further strengthens the hypothesis that innate immune reactions may strongly contribute to the pathogenesis of Alzheimer's disease (AD). The neuroinflammatory component of the disease, which has been for long the stepchild of AD research, is recently gaining increasing interest, instigated by findings which point to an involvement of inflammatory genes as risk factors for sporadic AD (Jones et al., 2010; Guerreiro et al., 2012; Jonsson et al., 2012). Microglial cells, representing the brain's innate immune defense, mount a sterile inflammatory reaction in response to Aβ deposition and most likely other immunostimulants in the degenerating brain (Lucin and Wyss Coray, 2009). One key feature of this reaction is the release of proinflammatory cytokines, which may further drive microglial inflammation, contribute to neuronal dysfunction and death, and also stimulate and recruit astroglial cells to the site of sterile inflammation. In their paper, the authors provide compelling evidence for a disease-promoting role of the interleukin 12, -23 signaling pathway. Genetic ablation of the common molecule p40, or the p35 and p19 components, decreased the cerebral Aβ load in APP/PS1 transgenic mice and ameliorated behavioral deficits. Likewise, intracerebroventricular administration of neutralizing p40 antibodies lowered soluble Aβ peptides and improved spatial memory. Importantly, the authors were able to identify resident microglia as responsible cells for interleukin 12, interleukin 23 generation, and a contribution from peripheral cells was proven unlikely. Another important finding is that genetic ablation of the interleukin-12/23 signaling pathway did not alter APP processing. Since the p40 receptor is strongly expressed on astrocytes, the authors suggest that microglial p40 may lead to Aβ reduction through the stimulation of astroglial Aβ uptake. However, astrocytes may interact with Aβ removal at multiple levels, including the release and lipidation of ApoE, which in turn can regulate microglial Aβ phagocytosis (Terwell et al., 2011).
Findings of increased p40 levels in human CSF from AD patients suggest that the interleukin-12/23 signaling pathway is activated in AD. However, further studies will have to identify the precise time course of this particular immunological pathway in AD before it may be exploited as a therapeutic target. Cerebral deposition of immunostimulating Aβ most likely occurs years, if not decades, before the presentation of clinical symptoms. While inflammation normally is of a self-limiting nature, in AD the persistent Aβ deposition acts as a constant stimulus which helps to establish a chronic inflammatory state. Given the detrimental effects of sustained neuroinflammation, a potential therapy will have to interfere with inflammatory mechanisms at the earliest time point possible, and therefore has to be of preventive rather than acute nature. While increasing evidence supports the hypothesis that innate immunity is intimately involved in AD progression, targets will have to be chosen wisely, and only those that can be blocked at pre- or very early disease states may ultimately provide therapeutic benefit.
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J, Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D, Pocklington A, Abraham R, Hollingworth P, Sims R, Gerrish A, Pahwa JS, Jones N, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, Heun R, Kölsch H, van den Bussche H, Heuser I, Peters O, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Rüther E, Carrasquillo MM, Pankratz VS, Younkin SG, Hardy J, O'Donovan MC, Owen MJ, Williams J. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS One. 2010;5(11):e13950. PubMed.
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K. Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):107-16. Epub 2012 Nov 14 PubMed.
Lucin KM, Wyss-Coray T. Immune activation in brain aging and neurodegeneration: too much or too little?. Neuron. 2009 Oct 15;64(1):110-22. PubMed.
Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson JÅ, Holtzman DM, Heneka MT. Critical role of astroglial apolipoprotein E and liver X receptor-α expression for microglial Aβ phagocytosis. J Neurosci. 2011 May 11;31(19):7049-59. PubMed.
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