A newly developed microscopy technique allows, for the first time, the visualization of more than 30 protein markers simultaneously in the human brain and uses bioinformatics to analyze their spatial relationships. In the process, the researchers have discovered a previously unknown population of immune cells in the brains of Alzheimer’s patients that is found almost exclusively in the vicinity of a specific type of pathological protein deposit.
The development could, in the future, bring about lasting changes not only in Alzheimer’s research but also in the investigation of tumors and other diseases. The method, known as CODEX-CNS, can visualize different cell types simultaneously, investigate their functional properties and, furthermore, analyze the spatial relationships between cells. The research findings have just been published in Nature Neuroscience.
“In principle, this method allows us to capture the entire cellular interplay in the human brain in a single image, including pathological changes and the interactions between cells,” explains lead author Dennis-Dominik Rosmus, who carried out the research at the Chair of Anatomy and Cell Biology at the Faculty of Medicine, University of Augsburg, and at the Institute of Anatomy, University of Leipzig, but is now based in Leipzig.
Widely applicable method
“We have used CODEX-CNS to examine the brains of people with Alzheimer’s disease, but the method can also be applied to other brain disorders,” explains Peter Wieghofer, Professor of Cellular Neuroanatomy at the Department of Anatomy and Cell Biology at the University of Augsburg. “With modifications, it can also be applied to other organs, meaning that in future it will be possible to compile various markers for specific research questions.
“It therefore has a very wide range of applications in medical research. For example, the retina is also part of the central nervous system and, like the brain, is populated by resident immune cells, the microglia, which are the focus of the current study.”
In particular, the method allows for the systematic investigation of how and which cells influence one another within the tissue. These neighborhood relationships are important not only in the brain for understanding neurodegenerative diseases, but also, for example, in cancer, to better understand tumor growth and immune responses.
New cell population identified in Alzheimer’s disease
By applying this method to the brain tissue of Alzheimer’s patients, the researchers made a crucial discovery: a specific group of disease-associated immune cells (known as microglia) that accumulate specifically in a particular form of typical Alzheimer’s protein deposits (amyloid-? plaques). These cells provide important clues as to how inflammatory processes and immune responses contribute to the development and progression of the disease. “The method opens up new possibilities for personalized medicine and targeted therapies,” Wieghofer adds.
Case study: Age-related macular degeneration
In Augsburg, Cavanagh Gohlich will continue to work with CODEX-CNS. She is pursuing her Ph.D. in Peter Wieghofer’s research group and will apply her experience with this method to age-related macular degeneration. She is a co-author of this publication and was involved in establishing CODEX-CNS at Oregon State University in Portland, U.S., under Prof. Dr. Bahareh Ajami. Gohlich is a Ph.D. student at the first Augsburg Research School of the Faculty of Medicine (AUGMENT).
Publication details
Paula Sanchez-Molina et al, Spatial proteomic analysis in human Alzheimer’s disease brains enables identification of microenvironment-dependent microglial cell states, Nature Neuroscience (2026). DOI: 10.1038/s41593-026-02267-3
Journal information:
Nature Neuroscience
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