Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer’s disease

Carolin Meyer, Theresa Niedermeier, Paul L. C. Feyen, Felix L. Strübing, Boris-Stephan Rauchmann, Katerina Karali, Johanna Gentz, Yannik E. Tillmann, Nicolas F. Landgraf, Svenja-Lotta Rumpf, Katharina Ochs, Karin Wind-Mark, Gloria Biechele, Jessica Wagner, Selim Guersel, Carolin I. Kurz, Meike Schweiger, Danilo Prtvar, Yuan Shi, Richard B. Banati, Guo-Jun Liu, Ryan J. Middleton, Gerda Mitteregger-Kretzschmar, Robert Perneczky, Thomas Koeglsperger, Jonas J. Neher, Sabina Tahirovic, Matthias Brendel, Jochen Herms and Lars Paeger ()
Additional contact information
Carolin Meyer: German Center for Neurodegenerative Diseases (DZNE)
Theresa Niedermeier: German Center for Neurodegenerative Diseases (DZNE)
Paul L. C. Feyen: German Center for Neurodegenerative Diseases (DZNE)
Felix L. Strübing: German Center for Neurodegenerative Diseases (DZNE)
Boris-Stephan Rauchmann: LMU Munich
Katerina Karali: German Center for Neurodegenerative Diseases (DZNE)
Johanna Gentz: German Center for Neurodegenerative Diseases (DZNE)
Yannik E. Tillmann: German Center for Neurodegenerative Diseases (DZNE)
Nicolas F. Landgraf: German Center for Neurodegenerative Diseases (DZNE)
Svenja-Lotta Rumpf: German Center for Neurodegenerative Diseases (DZNE)
Katharina Ochs: German Center for Neurodegenerative Diseases (DZNE)
Karin Wind-Mark: LMU Munich
Gloria Biechele: Ludwig-Maximilians-Universität
Jessica Wagner: German Center for Neurodegenerative Diseases (DZNE)
Selim Guersel: LMU Munich
Carolin I. Kurz: LMU Munich
Meike Schweiger: LMU Munich
Danilo Prtvar: German Center for Neurodegenerative Diseases (DZNE)
Yuan Shi: German Center for Neurodegenerative Diseases (DZNE)
Richard B. Banati: The University of Sydney
Guo-Jun Liu: The University of Sydney
Ryan J. Middleton: Australian Nuclear Science and Technology Organisation (ANSTO)
Gerda Mitteregger-Kretzschmar: Ludwig-Maximilians-Universität
Robert Perneczky: German Center for Neurodegenerative Diseases (DZNE)
Thomas Koeglsperger: German Center for Neurodegenerative Diseases (DZNE)
Jonas J. Neher: German Center for Neurodegenerative Diseases (DZNE)
Sabina Tahirovic: German Center for Neurodegenerative Diseases (DZNE)
Matthias Brendel: German Center for Neurodegenerative Diseases (DZNE)
Jochen Herms: German Center for Neurodegenerative Diseases (DZNE)
Lars Paeger: German Center for Neurodegenerative Diseases (DZNE)

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Alzheimer’s disease (AD) often begins with non-cognitive symptoms such as olfactory deficits, which can predict later cognitive decline, though the mechanisms remain unclear. Pathologically, the brainstem locus coeruleus (LC), the main source of the neurotransmitter noradrenalin (NA) modulating olfactory information processing is affected early. Here we show early and distinct loss of noradrenergic input to the olfactory bulb (OB) coinciding with impaired olfaction in an AD mouse model, before appearance of amyloid plaques. Mechanistically, OB microglia recognize and phagocytose LC axons. Reducing phagocytosis genetically preserves LC axons and olfaction. Prodromal AD patients display elevated TSPO-PET signals in the OB, similarly to AppNL-G-F mice. We further confirm early LC axon degeneration in post-mortem OBs in patients with early AD. Our findings reveal a mechanism linking early LC damage to hyposmia in AD, suggesting olfactory testing and neurocircuit imaging for early diagnosis and enable timely therapeutic intervention for Alzheimer’s disease.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-62500-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62500-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-62500-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().