Neurogenetics

The Department of Neurogenetics, founded in 1999, was closed on March 31, 2026. Since April 2026, Klaus-Armin Nave has continued his research at the Department of Neuropathology, Charité – Universitätsmedizin Berlin, alongside his new role as Emeritus Director at the Max Planck Institute for Multidisciplinary Sciences (MPI-NAT).

The electrical insulation of axons by glial cells represents one of the most complex cell–cell interactions in the nervous system and enables rapid neuronal communication over long distances. My research group has shown that myelin-forming glial cells of the central nervous system, oligodendrocytes, not only insulate long axons but also provide direct metabolic support as predominantly glycolytic cells. At the same time, the active lipid metabolism within myelin constitutes a previously underappreciated energy reserve of the brain. In the aging brain, the ultrastructure of myelin required for the transfer of pyruvate and lactate is frequently compromised, thereby representing an age-dependent risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD). In addition, we have demonstrated that oligodendrocytes themselves are a source of the AD-associated amyloid-β peptide.

My group investigates the development and aging of the nervous system, as well as the mechanisms underlying neurodegenerative diseases, using genetic and cell biological approaches. For many years, our work has focused on the biology of glial cells in the white matter tracts of the brain, spinal cord, and peripheral nerves—particularly Schwann cells and oligodendrocytes—and their interactions with neuronal processes, the axons. Despite their fundamental importance, key functions of glial cells remained poorly understood compared to neurons for a long time. Only with the advent of molecular genetic approaches, especially cell type–specific mutations in the mouse, have major conceptual advances become possible since the 1990s. This has led to a level of understanding of glial function that is comparable in scope to the classical discoveries of neuronal cell biology in the previous century.

A highly specialized class of glial cells ensheathes axons with a multilayered, compact membrane structure known as myelin. This myelination acts as electrical insulation and enables the rapid and energy-efficient propagation of nerve impulses—a prerequisite for normal motor and cognitive function (Nave, 2010; Nave and Werner, 2024). Our work at MPI-NAT identified the first axonal signaling molecules in the peripheral nervous system that regulate myelin growth by Schwann cells (Michailov et al., 2004). In contrast, the corresponding mechanisms in the central nervous system remain largely unknown. This raises fundamental questions: Which genetic programs have driven the evolution of myelination? How do oligodendrocytes sense axonal activity and caliber to generate the appropriate amount of myelin? And how are these processes regulated in time and space?

At the same time, myelin poses a challenge for the axon: by electrically insulating it, myelin restricts direct access to the extracellular environment and thus to immediate metabolic support. Indeed, myelinating glial cells are essential for the long-term survival of axons. We have shown that oligodendrocytes actively contribute to axonal energy supply by adjusting their metabolism and providing glycolytic products such as lactate as energy substrates (Fünfschilling et al., 2012; Saab et al., 2016). This tight axo-glial coupling enables continuous metabolic support of active axons. In addition, myelin lipids themselves can serve as a mobilizable energy reserve, contributing to the maintenance of brain energy homeostasis (Asadollahi et al., 2024).

In this context, we increasingly view myelin as fulfilling three complementary functions: as a support system, a metabolic reserve, and a potential risk factor for neurodegenerative disease. We have shown that disturbances in myelin structure and function are not only a consequence but can also represent an early risk factor for such disorders. This is particularly relevant for multiple sclerosis (Schaeffner et al., 2023) and Alzheimer’s disease (Depp et al., 2023). Our recent work further indicates that oligodendrocytes themselves may contribute to the production of amyloid-β (Sasmita et al., 2024), positioning them as active participants in Alzheimer’s pathology.

This functional complexity requires a sophisticated myelin architecture, including non-compact channel-like structures that allow direct exchange of metabolites between glial cells and axons (Chapple et al., 2026). A central focus of our research is to understand how stable these support structures are across the lifespan. Age-related alterations in myelin, as regularly observed by electron microscopy, may impair axonal support and thereby contribute to cognitive decline and the development of neurodegenerative diseases.

By analyzing neuron–glia interactions—particularly through genetic models in the mouse—our research contributes to a deeper understanding of the cellular basis of neurological and psychiatric disorders and helps to identify new therapeutic strategies.

Asadollahi, E., Trevisiol, A., ... and Nave, K.-A. (2024). Oligodendsroglial fatty acid metabolism as a central nervous system energy reserve. Nat. Neurosci. 27, 1934-1944.

Chapple, K....Nave, K.-A., and Edgar, J (2026). A Transport Route Across Myelin (TRAM) for motor-driven organelle transfer. Nat. Neurosci. in press

Depp, C., Sun, T., ...and Nave K-A (2023) Myelin dysfunction drives amyloid deposition in models of Alzheimer’s disease. Nature 618: 349-357.

Fünfschilling, U., Supplie, L.M., Mahad, D., ... and Nave, K.-A. (2012). Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485, 517-521.

Michailov. G., V., Sereda, M.W., ...and Nave, K.-A. (2004). Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 700-703.

Nave, K.-A. (2010). Myelination and support of axonal integrity by glia. Nature 468, 244-252

Nave, K.-A. and Werner H.B.(2021). Ensheathment and Myelination of Axons: Evolution of Glial Functions. Annu. Rev. Neurosci. 44:197-219.

Nave, K.-A., Asadollahi,E., Sasmita, A. (2023) Expanding the function of oligodendrocytes to brain energy metabolism. Curr. Opin. Neurobiol. 83:102782.

Saab, A.S., ... Kirchhoff, F., and Nave, K.-A. (2016). Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 91, 119-132

Sasmita, A.O., Depp, C., ...and Nave, K.-A. (2024). Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer's disease model mice. Nat. Neurosci. 27, 1668-1674.

Schäffner, E., ...Fledrich, R., Nave, K.-A, and Stassart, R., (2023) Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease. Nat. Neurosci. 26:1218-1228