Open Research Projects, Research

Expression pattern and function of IL-12 receptor in the central nervous system in neurodegeneration and aging

Prinicipal Investigator

Prof. Dr. Frank Heppner
PD Dr. Marina Jendrach

Scientific interest within the context of the graduate college

Our project directly aligns with the central mission of the Else Kröner-Fresenius Graduate College Re-Thinking Health, which aims to establish a novel, mechanistic understanding of health as an active, regulated biological state and to identify molecular targets for prevention. Rather than focusing solely on disease mechanisms, the project investigates how immune-mediated signaling pathways contribute to the maintenance of neuronal integrity and functional resilience in the central nervous system. Specifically, this project addresses the role of Interleukin-12 (IL-12) signaling in neurons and glial cells in the context of aging and neurodegeneration. By dissecting the cell type-specific functions of the IL-12 receptor, particularly in Parvalbumin-positive interneurons, the study explores whether immune-derived signals contribute to adaptive, health-preserving processes in the brain. This approach reflects the Graduate College’s conceptual framework that health is maintained by distinct molecular pathways, including those mediating adaptation to environmental and internal stressors.

Importantly, the project integrates both human and murine data to identify molecular signatures associated with resilient versus maladaptive neuroinflammatory responses. In doing so, it contributes to defining early deviations from a healthy state, a key objective of the program. Furthermore, by identifying cell-specific signaling mechanisms that modulate neuronal survival, network stability, and myelination, the project may uncover novel molecular targets for preventive strategies in age-associated neurodegenerative diseases such as Alzheimer’s disease. Overall, this work exemplifies the transition from a disease-centered to a health-centered research paradigm by investigating how immune-neuronal interactions shape brain health, resilience, and the prevention of neurodegenerative pathology.

Project description

Microglia, the resident myeloid cells of the central nervous system (CNS), undergo pronounced phenotypic changes during aging and in neurodegenerative disorders. While early microglial activation can exert neuroprotective effects, sustained activation promotes chronic neuroinflammation through the release of neurotoxic mediators, including pro-inflammatory cytokines.1,2 Interleukin-12 (IL-12) is one of these proinflammatory cytokines, produced primarily by activated microglia in the CNS. Elevated IL-12 levels have been reported in the brains of patients with Alzheimer’s disease (AD) as well as in AD-like mouse models.3,4

In acute neuroinflammatory conditions characterized by strong cytokine responses, such as multiple sclerosis, IL-12 has been shown to exert neuroprotective effects on neurons, though not on oligodendrocytes.5 In contrast, during chronic neuroinflammation, as observed in AD mouse models and likely also in aging, IL-12 deficiency results in a marked reduction of AD-like pathology, including decreased amyloid-β deposition and altered neuroinflammation.6,7 Notably, IL-12 deficiency confers neuroprotection in this context, particularly for Parvalbumin (PV)-positive GABAergic interneurons, a neuronal population that is especially vulnerable in early Aβ pathology.4,8

Preliminary data from our group indicate a region-specific expression pattern of the IL-12 receptor in neurons (Heppner lab, unpublished). Based on this, the first aim of the project is to systematically assess IL-12 receptor expression in murine and human brain tissue across aging and disease conditions. However, as IL-12 receptors are expressed not only on neurons but also on oligodendrocytes, conventional IL-12 knockout models do not allow discrimination between cell type-specific effects. Given that oligodendrocytes are responsible for myelination and that neuronal activity can influence this process,9 the observed neuroprotective phenotype in IL-12-deficient models may, at least in part, result from secondary effects on myelination. For example, IL-12-stimulated neurons can release trophic factors that support oligodendrocyte function.5 To address this limitation, the second aim is to selectively abrogate IL-12 signaling in PV-positive neurons by deleting the IL-12 receptor using a PV-Cre mouse model (constitutive deletion). This approach will enable a cell type-specific and temporally resolved analysis of IL-12 signaling in this vulnerable neuronal population during aging and in AD-like pathology.

Aim 1: Translational correlation of IL12 receptor expression. Models: IL12rb1 and rb2 expression in various existing mouse models and age groups and in human samples from the Charité Brain Bank; Methods: RNAscope; immunohistochemistry; confocal microscopy, image analysis

Aim 2: Effects of the loss of IL-12 signaling in PV interneurons in aging and AD-like mice. Models: PV-Cre.IL12rb2 and APPPS1.PV-Cre.IL12rb2 mice. Mouse colonies are established and animal permit is granted; Methods: Analysis of neuroinflammation, neuronal changes and Alzheimer’s pathology: protein extraction, Mesoscale/ELISA, immunohistochemistry, Western blot, myelinization, (electrophysiology in cooperation with the Geiger Lab).

Application details

References

  1. Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015; 16(6): 358-372.
  2. Cai Y, Liu J, Wang B, Sun M, Yang H. Microglia in the neuroinflammatory pathogenesis of Alzheimer’s disease and related therapeutic targets. Front Immunol.2022; 13: 856376.
  3. Bruno M, Bonomi CG, Castelli A, Izzi F, Placidi F, Falletti S, Mercuri NB, Motta C, Martorana A. Cerebrospinal fluid cytokine levels affect electroencephalographic activity in Alzheimer’s disease. J Alzheimers Dis Rep. 2025; 9: 25424823241306772.
  4. Schneeberger S, Kim SJ, Geesdorf MN, Friebel E, Eede P, Jendrach M, Boltengagen A, Braeuning C, Ruhwedel T, Hülsmeier AJ, Gimber N, Foerster M, Obst J, Andreadou M, Mundt S, Schmoranzer J, Prokop S, Kessler W, Kuhlmann T, Möbius W, Nave KA, Hornemann T, Becher B, Edgar JM, Karaiskos N, Kocks C, Rajewsky N, Heppner FL. Interleukin-12 signaling drives Alzheimer’s disease pathology through disrupting neuronal and oligodendrocyte homeostasis. Nat Aging. 2025; 5(4): 622-641.
  5. Andreadou M, Ingelfinger F, De Feo D, Cramer TLM, Tuzlak S, Friebel E, Schreiner B, Eede P, Schneeberger S, Geesdorf M, Ridder F, Welsh CA, Power L, Kirschenbaum D, Tyagarajan SK, Greter M, Heppner FL, Mundt S, Becher B. IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice. Nat Neurosci. 2023; 26(10): 1701-1712.
  6. 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; 18(12): 1812-1819.
  7. Eede P, Obst J, Benke E, Yvon-Durocher G, Richard BC, Gimber N, Schmoranzer J, Böddrich A, Wanker EE, Prokop S, Heppner FL. Interleukin-12/23 deficiency differentially affects pathology in male and female Alzheimer’s disease-like mice. EMBO Rep. 2020; 21(3): e48530.
  8. Chen YB, Jiang B, Zhuang K, Wang H, Peng HM, Zhong BW, Xie WT, Chen KW, Zou TT, Wang Y, Yang HL, Yang Q, Zhou J, Zhong L, Zhang LH, Zhang J. Hyperactivity of subicular parvalbumin interneurons drives early amyloid pathology and cognitive deficits in Alzheimer’s disease. Mol Psychiatry. 2025; 30(12): 5777-5789.
  9. Zhou Y, Zhang J. Neuronal activity and remyelination: new insights into the molecular mechanisms and therapeutic advancements. Front Cell Dev Biol. 2023; 11: 1221890.