TY  - JOUR
AU  - Meyer, Carolin
AU  - Niedermeier, Theresa
AU  - Feyen, Paul L C
AU  - Strübing, Felix L
AU  - Rauchmann, Boris Stephan
AU  - Karali, Katerina
AU  - Gentz, Johanna
AU  - Tillmann, Yannik
AU  - Landgraf, Nicolas Friedrich
AU  - Rumpf, Svenja-Lotta
AU  - Ochs, Katharina
AU  - Wind-Mark, Karin
AU  - Biechele, Gloria
AU  - Wagner, Jessica
AU  - Guersel, Selim
AU  - Kurz, Carolin
AU  - Schweiger, Meike
AU  - Prtvar, Danilo
AU  - Shi, Yuan
AU  - Banati, Richard B
AU  - Liu, Guo-Jun
AU  - Middleton, Ryan J
AU  - Mitteregger-Kretzschmar, Gerda
AU  - Perneczky, Robert
AU  - Koeglsperger, Thomas
AU  - Neher, Jonas J
AU  - Tahirovic, Sabina
AU  - Brendel, Matthias
AU  - Herms, Jochen
AU  - Paeger, Lars
TI  - Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer's disease.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-00939
SP  - 7338
PY  - 2025
AB  - 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.
KW  - Alzheimer Disease: pathology
KW  - Alzheimer Disease: physiopathology
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: diagnostic imaging
KW  - Alzheimer Disease: complications
KW  - Locus Coeruleus: pathology
KW  - Locus Coeruleus: metabolism
KW  - Animals
KW  - Humans
KW  - Axons: pathology
KW  - Axons: metabolism
KW  - Olfactory Bulb: pathology
KW  - Olfactory Bulb: metabolism
KW  - Olfactory Bulb: physiopathology
KW  - Mice
KW  - Male
KW  - Disease Models, Animal
KW  - Female
KW  - Mice, Transgenic
KW  - Microglia: metabolism
KW  - Microglia: pathology
KW  - Norepinephrine: metabolism
KW  - Aged
KW  - Phagocytosis
KW  - Adrenergic Neurons: pathology
KW  - Adrenergic Neurons: metabolism
KW  - Olfaction Disorders: pathology
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Smell: physiology
KW  - Aged, 80 and over
KW  - Mice, Inbred C57BL
KW  - Plaque, Amyloid: pathology
KW  - Norepinephrine (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40781079
C2  - pmc:PMC12334674
DO  - DOI:10.1038/s41467-025-62500-8
UR  - https://pub.dzne.de/record/280284
ER  -