ORCID: https://orcid.org/0009-0009-2257-5394; Feyen, Paul L. C.; Strübing, Felix L. ORCID: https://orcid.org/0000-0002-9436-6294; Rauchmann, Boris-Stephan ORCID: https://orcid.org/0000-0003-4547-6240; Karali, Katerina; Gentz, Johanna; Tillmann, Yannik E. ORCID: https://orcid.org/0009-0005-0828-3425; Landgraf, Nicolas F. ORCID: https://orcid.org/0009-0003-9134-6575; Rumpf, Svenja-Lotta; Ochs, Katharina; Wind-Mark, Karin ORCID: https://orcid.org/0000-0002-5461-1873; Biechele, Gloria ORCID: https://orcid.org/0009-0008-5161-9571; Wagner, Jessica; Guersel, Selim ORCID: https://orcid.org/0000-0001-6714-5827; Kurz, Carolin I. ORCID: https://orcid.org/0000-0003-4299-6240; Schweiger, Meike; Prtvar, Danilo; Shi, Yuan ORCID: https://orcid.org/0000-0001-6135-1830; Banati, Richard B. ORCID: https://orcid.org/0000-0003-3558-597X; Liu, Guo-Jun ORCID: https://orcid.org/0000-0002-4278-8372; Middleton, Ryan J.; Mitteregger-Kretzschmar, Gerda; Perneczky, Robert ORCID: https://orcid.org/0000-0003-1981-7435; Koeglsperger, Thomas ORCID: https://orcid.org/0000-0001-6101-0323; Neher, Jonas J. ORCID: https://orcid.org/0000-0003-1346-8924; Tahirovic, Sabina ORCID: https://orcid.org/0000-0003-4403-9559; Brendel, Matthias ORCID: https://orcid.org/0000-0002-9247-2843; Herms, Jochen ORCID: https://orcid.org/0000-0002-6201-1042 und Paeger, Lars ORCID: https://orcid.org/0000-0001-8716-3483
(2025):
Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer’s disease.
In: Nature Communications, Bd. 16, 7338
[PDF, 7MB]
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.
| Dokumententyp: | Zeitschriftenartikel |
|---|---|
| EU Funded Grant Agreement Number: | 101132356 |
| Fakultät: | Medizin > Munich Cluster for Systems Neurology (SyNergy) |
| Themengebiete: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit |
| URN: | urn:nbn:de:bvb:19-epub-129884-8 |
| ISSN: | 2041-1723 |
| Sprache: | Englisch |
| Dokumenten ID: | 129884 |
| Datum der Veröffentlichung auf Open Access LMU: | 28. Nov. 2025 13:48 |
| Letzte Änderungen: | 28. Nov. 2025 13:48 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |
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