KFO 177: Innate immunity in chronic neurodegeneration
Zusammenfassung der Projektergebnisse
For decades research on neurodegenerative disorders was mainly focussed on neurons and their networks. Disease-associated changes of their immediate environment and in particular micro- and astroglial cells were long regarded as bystander reaction of unknown or minor significance for disease pathogenesis and progression. Both, microglia as wel as astrocytes represent the innate immune system of the central nervous system. The clinical research group (CRG) 177, entitled „Innate Immunity in chronic neurodegeneration“ was initiated in order to investigate the potential diseasecausing and modifying role of innate immune factors in neurodegenerative disorders including but not restricted to Alzheimer’s disease, epilepsy and multiple sclerosis. Using an epilepsy model PI’s Beck & Becker analyzed the influence of immune mediators and in particular the cytokine tumor necrosis factor alpha (TNFα) for its ability to modulate synaptic function, axonal integrity and neurons. Importantly, the project identified a mechanism by which TNFα increased intracellular Zn2+ concentrations thereby altering the expression of a distinct voltage-dependent T-type calcium channel mRNA (CaV3.2) and susceptibility for epilepsy. PI Fuhrmann further characterised the microglial surface receptor CX3CR1, known to modulate neuronal integrity in a mouse model of Alzheimer’s disease (AD). Using two-photon in vivo imaging this project found that CX3CR1-deficiency ameliorated spine density and microglia spine touch with an overall beneficial impact on object recognition. Showing that the genetic modulation of a microglial surface receptor directly impacts on murine memory performance underlined the important connection between neurons and their glial environment. The project coordinated by Hartmann and Coch showed that targeting of RIG-I and MDA-5 by 5´-triphosphate RNA or synthetic double-stranded (ds) RNA (poly(I:C)) leads to disease amelioration and induction of type I IFNs in an experimentally-induced autoimmune encephalomyelitis model of multiple sclerosis. Unfortunately, this couldn’t be translated in a clinical trial as initially planned and will have to be tested in a further, CRG-independent project. The project let by Heneka identified a mechanism by which the nuclear hormone receptor liver X receptor modulates microglial β-amlyoid (Aβ) phagocytosis through the lipidation of ApoE, thereby shedding light on the functional impact of the most prevalent risk gene for sporadic AD. Klotz & Klockgether’s project identified PPARγ, in myeloid cells as a potential target for attenuating myeloid cell-mediated autoimmunity and ultimately organ damage. PI’s Latz & Hornung, in collaboration with Heneka investigated how NLRRP3 skews microglia in a proinflammatory, clearance-impaired phenotype that accounts for dendritic spine loss, suppression of long-term potentiation and memory decline in APP/PS1 transgenic mice, an established AD model. During this project, the collaborating groups developed the first assay to quantitatively assess in vivo Aβ phagocytosis by microglia, that now represents the gold-standard in the field. Addressing the impact of a further soluble immune mediator, Müller delineated by which mechanisms the chemokine CXCR3 is modulating microglia functions, including migration and Aβ phagocytosis in vitro and in vivo. Together with the above projects this investigation further supported the hypothesis that chronic inflammation leads to compromized microglial clearance function and ultimately causes cognitive dysfunction in rodent models of AD. Thus, strategies, which restore beneficial microglial functions hold therapeutic promise. In this regard, PI Neumann showed that human Siglec-11 ectopically expressed on murine microglia interacts with sialic acid residues on neurons, reduces LPS-induced proinflammatory gene transcription and alleviates microglial neurotoxicity. Last but not least PI Walter found that the triggering receptor expressed on myeloid cells 2 (TREM2) represents a novel protein substrates of γ-secretase in microglia, and accounts for microglial Ca2+ signaling, recognition of neuronal debris and phagocytosis. Importantly, loss of γ-secretase activity or genetically (FAD mutations) altered γ-secretase function showed that human mutations in the γ-secretase-complex not only affect APP processing but also microglial clearance functions.
Projektbezogene Publikationen (Auswahl)
- NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013)
Heneka, M. T. et al.
(Siehe online unter https://doi.org/10.1038/nature11729) - Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5’- diphosphates. Nature 514, 372–375 (2014)
Goubau, D. et al.
(Siehe online unter https://doi.org/10.1038/nature13590) - Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus. Nat. Commun. 6, 6031 (2015)
Johnson, M. R. et al.
(Siehe online unter https://doi.org/10.1038/ncomms7031) - Zinc regulates a key transcriptional pathway for epileptogenesis via metal-regulatory transcription factor 1. Nat. Commun. 6, 8688 (2015)
van Loo, K. M. J. et al.
(Siehe online unter https://doi.org/10.1038/ncomms9688)
