MiNAD - The Microglia-Neuron Interaction in Aging and Neurodegeneration

• Applicant: Dr. Christiane Hartmann
• Subject Area: Biogerontology and Geriatric Medicine ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570238073

With increasing age, the central nervous system undergoes considerable structural, functional and molecular changes. Microglia, which as resident immune cells of the brain play a central role in maintaining neuronal homeostasis, are particularly affected. They are involved in a dynamic, bidirectional exchange with neurons and significantly influence their function. In the adult brain, they contribute to immune surveillance, inflammation modulation and thus to the maintenance of neuronal functionality through continuous “surveilling”. With increasing age, microglia show a change in their transcriptome towards a pro-inflammatory phenotype, characterized by reduced homeostasis, decreased resilience and chronic activation. These changes directly influence the functions and vitality of neighboring neurons. We hypothesize that these microglial, age-related changes may contribute significantly to the pathogenesis of neurodegenerative diseases. The aim of the proposed project is to systematically investigate the reciprocal interactions between microglia and neurons under the influence of cellular aging. The focus is on the question of how altered microglia affect neurons - and vice versa. For this purpose, a human co-culture system is used in which microglia and motor neurons are differentiated from induced pluripotent stem cells. Both cells from healthy donors and those from patients with Hutchinson-Gilford Progeria syndrome, a model of accelerated ageing, are used. The experimental analyses focus on three central questions: 1. Do aged microglia or neurons accelerate the aging process? To this end, the biological age of the specific cell types is measured using a quantitative “AgeScore” based on classic age markers. A special focus is placed on the mutual influence of both cell types. 2. To what extent does age influence the functionality of microglia and neurons? - Phagocytosis assays and multi-electrode arrays are used to test cellular performance under aging conditions. The aim is to uncover changes in interaction behavior. 3. Are age-related cellular changes sufficient to trigger or promote neurodegenerative processes? Morphological studies, cytokine profiling and transcriptome analysis will be used to identify pathophysiological mechanisms underlying microglial-neuronal dysfunction in aging. The project aims to gain new insights into the role of aging in microglial-neuronal networks and to identify potential therapeutic targets for age-associated neurodegenerative diseases.

• DFG Programme: Research Grants