Klotho is an aging regulator and pleiotropic hormone, primarily produced in the kidney and choroid plexus of the brain. Previous studies in model organisms demonstrated that elevation of Klotho levels extend lifespan and improve cognition while disruption accelerates aging and induces cognitive decline. In our project we will combine studies in humans and mice to investigate the mechanisms by which Klotho regulates brain function and whether interventions addressed to enhance its expression also improve cognition and expand neural resource. Our main goal is to explore whether the Klotho secretory system can be targeted as reserve in normal aging or resilience in the face of manifest pathology.
Dr. Maria Andres-Alonso
Dr. rer. nat Maria Andres-Alonso obtained her degree in Biology at the University of Navarre, Spain. After obtaining her master´s degree in Neuroscience at University College London, UK, she joined the laboratory of Dr. Anna Fejtova and Dr. Eckart Gundelfinger the Leibniz Institute for Neurobiology (LIN) where she performed her doctoral studies within a Marie Curie ITN programme coordinated by Dr. Michael Kreutz. She is currently working as a senior post-doctoral researcher in the research group Neuroplasticity leaded by Dr. Michael Kreutz at LIN. Her research interests are directed towards understanding the role degradative organelles at synaptic sites and function, and the contribution of microsecretory systems in maintaining proteostasis of synaptic membrane proteins.
Prof. Dr. med. Emrah Düzel
Emrah Düzel has trained as a neurologist in Germany (in Bonn and Magdeburg). He is working as a cognitive neurologist on the functional anatomy of human episodic memory networks, neuromodulatory circuits, their clinical and mechanistic alterations in aging and neurodegeneration and their scope for plasticity. He leads the Institute of Cognitive Neurology and Dementia Research and Memory Clinic at the OvG University Magdeburg. As speaker of the Magdeburg site of the German Center for Neurodegenerative Diseases (DZNE, Helmholtz Society), he supports the implementation and analysis of imaging and cognition measures for early Alzheimer’s disease. He is also a part time group leader at the Institute of Cognitive Neuroscience at the Univ. College London, a fellow of the Max-Planck School of Cognition and co-founder of the digital health start-up neotiv. Within the newly founded German Network of Memory Clinics, he coordinates a working group on Digital Health and Telemedicine.
Dr. Michael R. Kreutz
Michael R. Kreutz is head of the Neuroplasticity research group at the Leibniz Institute for Neurobiology and he has a second affiliation at the Center for Molecular Neurobiology (ZMNH) in Hamburg where he is heading the Leibniz Group ‘Dendritic Organelles and Synaptic Function’. His research interest is in synapse biology. His work is concerned with fundamental questions on how synapses communicate with the nucleus, how gene activity-dependent gene expression feeds back to synaptic function and how this is related to the formation of a cellular engram and last but not least how the nanoscale organization of the synapse determines functional properties in the context of learning and memory.
Dr. Guilherme Gomes
I am a Brazilian neuroscientist member of the Research Group Neuroplasticity (LIN). I am interested on the molecular players that give rise to complex behaviors., and over the past 10 years I have been focusing on how NMDAR signaling controls the expression of plasticity-related genes, both in health and disease. As a member of the CRC1436 I am part of project A02, A04 and Z01, and my goal is to provide state-of-the-art methods for engram detection and manipulation to the CRC community
Dr. Rajeev Raman
Rajeev Raman is originally from Ranchi, Jharkhand, India. He obtained his Ph.D. at the Center for Cellular and Molecular Biology (CCMB), Hyderabad, India. Since January 2016, he is working as a scientific employee at NPlast, (Dr Michael Kreutz Group, LIN, Magdeburg). Rajeev contributes to his work with a lot of experience and competence in protein biochemistry.
Dr. Pingan Yuanxiang
My name is PingAn YuanXiang and graduated from Shanghai, China. I studied in the major of Neurobiology at the Fudan University in Shanghai and completed my Ph.D. thesis in 2012.
Since 2013 I work as a research scientist in Nplast at the LIN. My expertise is electrophysiology including field recordings and single-cell patch clamp and also combines with cell biological techniques. My main interest is related to molecular mechanisms of synaptic plasticity and aging regulator in brain function.
What do we know about Klotho?
The anti-aging hormone Klotho was identified serendipitously in a search for genes that regulate lifespan (Kuro-o et al., 1997). Mutant mice lacking the klotho gene exhibit phenotypes that resemble in many aspects human aging (Kuro-o et al., 1997; Kurosu et al., 2005) like impaired cognitive function among others.
The klotho gene encodes a single-pass transmembrane glycoprotein that consists of a short intracellular domain and larger extracellular domain. The proteolytic cleavage of the extracellular domain of Klotho by members of the ADAM family (Bloch et al., 2009) result in the release of smaller fragments into the blood circulation. These fragments are also found in urine and cerebrospinal fluid. Once released from the cell membrane, Klotho exerts its biological effects on organs and different tissues, thus functioning as a circulating hormone.
Which is the available evidence that connects Klotho to cognitive function?
Several lines of evidence suggest that targeting the Klotho endocrine axis might have therapeutic benefit in a variety of age-related conditions, including cognitive decline. The increase of Klotho levels in mice extend their lifespan and enhances hippocampal-dependent learning and memory (Dubal et al., 2014; Dubal et al., 2015). In humans the Klotho-VS variant of the klotho gene, which is associated with increased Klotho levels in serum, has been shown to also enhance cognition (Arking et al., 2002; Cararo-Lopes et al., 2017).
Though the cellular and molecular targets that underlie Klotho-dependent effect in the brain are unknown, Klotho is reported to elevate total and synaptic GluN2B protein levels (a N-methyl-D-aspartate receptor (NMDAR) subunit) (Cararo-Lopes et al., 2017). Additionally, recent evidence suggests that Klotho acts as a regulator of postnatal neurogenesis in the adult dentate gyrus, where it is also expressed (Masso et al., 2015). Thus, Klotho might promote, either dependent or independent of GluN2B NMDAR signalling, adult hippocampal neurogenesis and hippocampal dependent cognition.
The goals of our project
In studies performed in humans and mice we want to investigate by which mechanisms Klotho regulates brain function and whether interventions that aim to enhance Klotho expression such as physical activity improve cognition and expand neural resource. We will test whether targeting the Klotho endocrine axis can be a reserve in old age and provides resilience in the presence of manifest pathology.
Which sources of Klotho are relevant for cognition and brain function?
At present it is unclear which of the different Klotho sources have an impact on brain function and cognition. We will address this by using different region-specific Klotho mutant mouse lines, in which we will study cognitive function and synaptic plasticity. In this way we will assess the role of different Klotho sources i.e. neuronal, cleaved and secreted, generated from different brain areas and/or cell populations. Behaviour analysis of these lines will also allow us to compare results in mouse to those in humans.
Identification of Klotho molecular targets in the brain and regulation of Klotho expression
Based on previous studies, we will look at the abundance and dynamics of synaptic and extrasynaptic GluN2B NMDA receptors as well as adult neurogenesis in the dentate gyrus upon increased levels of Klotho. These will be achieved by exogenous administration of Klotho and/or by placing mice under conditions of physical activity, which has been shown to increase Klotho levels in the blood.
Based on our own preliminary work, we will study the molecular mechanism that regulates klotho gene expression by investigating the methylation of its promoter and we will test available small molecules termed as Klotho inducers to enhance its expression in the brain.
Klotho serum levels, physical activity and cognitive function in humans
Experiment with human blood samples will determine the effects of the exercise intervention on the serum levels of Klotho like previously done in mice (see above) and we will determine the relationship between hippocampal plasticity and Klotho levels, and whether this relationship is altered in pathology. Similarly, we will also test the hypothesis that higher levels of Klotho and the presence of the Klotho-VS variant, associate to increased Klotho levels in serum, enhance experience-dependent brain plasticity particularly in the presence of pathology.
A look into the future
The outcome of this project will set up the ground for assessing the true potential of Klotho as reserve in aging and resilience in the face of manifest pathology. We will be able to understand whether Klotho might be use to boost cognitive function under these conditions and what are the mechanisms involved. Altogether this will serve to foster the translational impact of the project towards clinical applications in the near future.
Publications of the project A04
Jacob-induced transcriptional inactivation of CREB promotes Aβ-induced synapse loss in Alzheimer’s disease
K. M Grochowska, G. M Gomes, R. Raman, R. Kaushik, L. Sosulina, H. Kaneko, A. M Oelschlegel, P. Yuanxiang, I. Reyes-Resina, G. Bayraktar, S. Samer, C. Spilker, M. S Woo, M. Morawski, J. Goldschmidt, M. A Friese, S. Rossner, G. Navarro, S….
Emrah Düzel, Gabriel Ziegler, David Berron, Anne Maass, Hartmut Schütze, Arturo Cardenas-Blanco, Wenzel Glanz, Coraline Metzger, Laura Dobisch, Martin Reuter, Annika Spottke, Frederic Brosseron, Klaus Fliessbach, Michael T Heneka, Christoph Laske, Oliver Peters, Josef Priller, Eike Jakob Spruth, Alfredo Ramirez,…
Katarzyna M Grochowska, Maria Andres-Alonso, Anna Karpova, Michael R Kreutz EMBO J (2022)
Fully automated deep learning-based localization and segmentation of the locus coeruleus in aging and Parkinson’s disease using neuromelanin-sensitive MRI
Max Dünnwald, Philipp Ernst, Emrah Düzel, Klaus Tönnies, Matthew J. Betts & Steffen Oeltze-Jafra International Journal of Computer Assisted Radiology and Surgery (2021)
Multiomics of synaptic junctions reveals altered lipid metabolism and signaling following environmental enrichment
Maximilian Borgmeyer, Cristina Coman, Canan Has, Hans-Frieder Schött, Tingting Li, Philipp Westhoff, Yam F H Cheung, Nils Hoffmann, PingAn Yuanxiang, Thomas Behnisch, Guilherme M Gomes, Mael Dumenieu, Michaela Schweizer, Michaela Chocholoušková, Michal Holčapek, Marina Mikhaylova, Michael R Kreutz, Robert Ahrends Cell Rep (2021)
Dendritic Kv4.2 potassium channels selectively mediate spatial pattern separation in the dentate gyrus
Marie Oulé, Erika Atucha, Tenyse M Wells, Tamar Macharadze, Magdalena M Sauvage, Michael R Kreutz, Jeffrey Lopez-Rojas iScience (2021)