Molecular Mechanisms of Neurodegeneration
Research group of the Department of Psychiatry and Psychotherapy
We are interested in the molecular mechanisms underlying neurodegenerative disorders, in particular Alzheimer’s disease (AD). We employ a variety of neuropathological, molecular biology and biochemical methods. We further use mouse models of AD to investigate the relationship between learning- and memory deficits and associated pathological alterations in the brain.
Selected current projects
The role of environmental factors in the development of Alzheimer’s disease
Several recent studies investigate the influence of environmental factors such as physical activity or nutritional factors on the course of Alzheimer’s disease (AD) in transgenic mouse models. We use the so-called “Enriched Environment” paradigm, providing a stimulating environment due to the presence of running wheels or various toys. We were able to detect that increased physical activity is associated with a considerable improvement in learning and memory performance, an amelioration of neuron loss and an increased neurogenesis rate in these mice (e.g. Hüttenrauch et al., Transl Psych 2016; Gerberding et al., ASN Neuro 2019; Stazi and Wirths, Behav Brain Res 2021). Recently, we were able to show that nutritional factors such as caffeine consumption exert beneficial effects on learning and memory in animal models (Stazi et al., Cell Mol Life Sci 2022; Stazi et al., Eur Arch Psych Clin Neurosci 2023; Stazi et al., Int J Mol Sci 2023).
References
- Hüttenrauch M., Brauß A., Kurdakova A., Borgers H., Klinker F., Liebetanz D., Salinas-Riester G., Wiltfang J., Klafki H.W., Wirths, O. (2016) Physical activity delays hippocampal neurodegeneration and rescues memory deficits in an Alzheimer disease mouse model. Translational Psychiatry, 6:e800; https://doi.org/10.1038/tp.2016.65
- Hüttenrauch M., Salinas G., Wirths O. (2016) Effects of long-term environmental enrichment on anxiety, memory, hippocampal plasticity and overall brain gene expression in C57BL6 mice. Frontiers in Molecular Neuroscience, 9:62; https://doi.org/10.3389/fnmol.2016.00062
- Gerberding A.-L., Zampar S., Stazi M., Liebetanz D., Wirths O. (2019) Physical activity ameliorates impaired hippocampal neurogenesis in the Tg4-42 mouse model of Alzheimer’s disease. ASN Neuro, 1759091419892692; https://doi.org/10.1177/1759091419892692.
- Stazi M., Wirths O. (2021) Physical activity and cognitive stimulation ameliorate learning and motor deficits in a transgenic mouse model of Alzheimer’s disease. Behavioural Brain Research, 397: 112951; https://doi.org/10.1016/j.bbr.2020.112951
- Stazi M., Lehmann S., Sakib M.S., Pena-Centeno T., Büschgens L., Fischer A., Weggen S., Wirths O. (2022) Long-term caffeine treatment of Alzheimer mouse models ameliorates behavioural deficits and neuron loss and promotes cellular and molecular markers of neurogenesis. Cellular and Molecular Life Sciences, 79(1): 55; https://doi.org/10.1007/s00018-021-04062-8
- Stazi M., Zampar S., Nadolny M., Büschgens L., Meyer T., Wirths O. (2023) Combined long-term enriched environment and caffeine supplementation improve memory function in C57Bl6 mice. European Archives of Psychiatry and Clinical Neuroscience, 273: 269-281; https://doi.org/10.1007/s00406-022-01431-7
- Stazi M., Zampar S., Klafki H.W., Meyer T., Wirths O. (2023) A combination of caffeine supplementation and enriched environment in Alzheimer's disease mouse model. International Journal of Molecular Sciences, 24(3): 2155; https://doi.org/10.3390/ijms24032155
Role of N-terminal modified Abeta peptides in Alzheimer’s disease
The deposition of so-called amyloid-beta (Abeta) peptides in the form of extracellular plaques is one of the major neuropathological hallmarks of Alzheimer’s disease (AD). In addition to the full-length Abeta1-40 and Abeta1-42 peptides, which are generated by sequential of the amyloid precursor protein (APP) by beta- and gamma-secretase, further N-terminal modified peptide variants have been identified (Wirths and Zampar, Expert Opin Ther Targets 2019). Among these are truncated Abeta peptides starting with the amino acid phenylalanine at position 4 (Abeta4-x), which have been identified in brain samples from AD patients and AD mouse models (Wirths et al., Alzheimers Res Ther 2017; Zampar et al., Neuropathol Appl Neurobiol 2020).; Bader et al., Life 2023), as well as N-terminally elongated species (such as Abeta-3-40) (Klafki et al., Int J Mol Sci 2020; Klafki et al., J Neurochem 2022). Recently, we identified the metalloprotease ADAMTS4 as an enzyme that is involved in the generation of Abeta4-x peptides and we were able to show that a lack of ADAMTS4 results in a strongly reduced generation of Abeta4-x peptides (Walter et al., Acta Neuropathol 2019). We are further interested in the potential influence of these modified peptides on myelin (Depp et al., Nature 2023) as ADAMTS4 is highly expressed in oligodendrocytes in the brain.
References
- Wirths O., Walter S., Kraus I., Klafki H.W., Stazi M., Oberstein T., Ghiso J., Wiltfang J., Bayer T.A., Weggen S. (2017) N-truncated Aß4-x peptides in sporadic Alzheimer's disease cases and transgenic Alzheimer mouse models. Alzheimer’s Research & Therapy, 9(1): 80 https://doi.org/10.1186/s13195-017-0309-z
- Wirths O., Zampar S. (2019) Emerging roles of N- and C-terminally truncated Aß peptides in Alzheimer’s disease. Expert Opinion on Therapeutic Targets, 23(12): 991-1004; https://doi.org/10.1080/14728222.2019.1702972.
- Walter S., Jumpertz T., Hüttenrauch M., Ogorek I., Gerber H., Storck S.E., Zampar S., Dimitrov M., Lehmann S., Lepka C., Berndt C., Wiltfang J., Becker-Pauly C., Beher D., Pietrzik C.U., Fraering P., Wirths O*. and Weggen S*. (2019) The metalloprotease ADAMTS4 generates N-truncated Aß4-x peptides and marks oligodendrocytes as a pro-amyloidogenic cell lineage in Alzheimer’s disease. Acta Neuropathologica, 137: 239-257 (*corresponding authors) https://doi.org/10.1007/s00401-018-1929-5
- Zampar S., Klafki H.W., Sritharen K, Bayer T.A., Wiltfang J., Rostagno A., Ghiso J., Miles L.A., Wirths O. (2020) N-terminal heterogeneity of parenchymal and vascular amyloid-b deposits in Alzheimer’s disease. Neuropathology Applied Neurobiology, 46: 273-285; https://doi.org/10.1111/nan.12637.
- Klafki H.W., Wirths O., Mollenhauer B., Liepold T., Rieper P., Esselmann H., Vogelgsang J., Wiltfang J., Jahn O. (2022) Detection and quantification of Aß-3-40 (APP669-711) in cerebrospinal fluid. Journal of Neurochemistry, 160: 578-589; https://doi.org/10.1111/jnc.15571.
- Klafki H.W., Morgado B., Wirths O., Jahn O., Bauer C., Schuchhardt J., Wiltfang J. (2022) Is plasma amyloid-b 1-42/1-40 a better biomarker for Alzheimer’s disease than Abx-42/x-40? Fluids and Barriers of the CNS, 19(1): 96; https://doi.org/10.1186/s12987-022-00390-4
- Bader A.S., Gnädig M.U., Fricke M., Büschgens L., Berger L.J., Klafi H.W., Meyer T., Jahn O., Weggen S., Wirths O. (2023) Brain region-specific differences in amyloid-b plaque composition in 5XFAD mice.Life, 13: 1053; https://doi.org/10.3390/life13041053
- Depp C., Sun T., Sasmita A.O., Spieth L., Berghoff S.A., Nazarenko T., Overhoff K., Steixner-Kumar A.A., Subramanian S., Arinrad S., Ruhwedel T., Möbius W., Göbbels S., Saher G., Werner H.B., Damkou A., Zampar S., Wirths O., Thalmann M., Simons M., Saito T., Saido T., Krueger-Burg D., Kawaguchi R., Willem M., Haass C., Geschwind D., Ehrenreich H., Stassart R., Nave K.-A. (2023) Myelin dysfunction drives amyloid deposition in mouse models of Alzheimer’s disease. Nature, 613: 349-357,DOI: 10.1038/s41586-023-06120-6
Role of signal transduction cascades in inflammatory processes in Alzheimer’s disease
Increasing evidence suggests that neuroinflammation contributes to progression and severity of AD. Activated microglial cells cluster around beta-amyloid deposits and seem to play a role in their clearance via phagocytosis. (Hüttenrauch et al., Acta Neuropathol Commun 2018; Aichholzer et al., Alzheimers Res Ther 2021). The so-called STAT proteins (signal transducer and activator of transcription) are important transcription factors, (Menon et al. BBA – Mol Cell Res 2021; Menon et al., Cell Commun Signal 2022; Remling et al. Cell Commun Signal 2023), which might be involved in the pathophysiological changes underlying AD. We aim to investigate the function of these STAT proteins in the context of AD with appropriate transgenic mouse models, with a focus of their specific role in microglial cells.
References
- Hüttenrauch M., Ogorek I., Klafki H.W., Otto M., Stadelmann C., Weggen S., Wiltfang J. Wirths O. (2018) Glycoprotein NMB: a novel Alzheimer’s disease associated marker expressed in a subset of activated microglia. Acta Neuropathologica Communications, 6(1): 108; https://doi.org/10.1186/s40478-018-0612-3
- Aichholzer F., Klafki H.W., Ogorek I., Vogelgsang J., Wiltfang J., Scherbaum N., Weggen S., Wirths O. (2021) Evaluation of cerebrospinal fluid glycoprotein NMB (GPNMB) as a potential biomarker for Alzheimer’s disease. Alzheimer’s Research & Therapy, 13: 94; https://doi.org/10.1186/s13195-021-00828-1
- Menon P.R., Doudin A., Gregus A., Wirths O., Staab J., Meyer T. (2021) The anti-parallel dimer conformation of STAT3 is required for the inactivation of cytokine signal transduction. Biochimica et Biophysica Acta – Molecular Cell Research, 1868(12): 119118; https://doi.org/10.1016/j.bbamcr.2021.119118
- Menon P.R., Staab J., Gregus A., Wirths O., Meyer T. (2022) An inhibitory effect on the nuclear import of phospho-STAT1 by its unphosphorylated form. Cell Communication & Signaling, 20(1):42 https://doi.org/10.1186/s12964-022-00841-3
- Remling L., Gregus A., Wirths O., Meyer T., Staab J. (2023) A novel interface between the N-terminal and coiled‑coil domain of STAT1 functions in an autoinhibitory manner. Cell Communication & Signaling, 21: 170; https://doi.org/10.1186/s12964-023-01124-1.
Contact
Research Group Leader
Prof. Dr. Oliver Wirths
+49 551 3965669
e-mail: owirths(at)gwdg.de
Publications: https://pubmed.ncbi.nlm.nih.gov/?term=wirths-o