Journal Article

DKFZ-2025-01663

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer's disease.

Meyer, C. ; Niedermeier, T. ; Feyen, P. L. C. ; Strübing, F. L. ; Rauchmann, B.-S. ; Karali, K. ; Gentz, J. ; Tillmann, Y. E. ; Landgraf, N. F. ; Rumpf, S.-L. ; Ochs, K. ; Wind-Mark, K. ; Biechele, G. ; Wagner, J. ; Guersel, S. ; Kurz, C. I. ; Schweiger, M. ; Prtvar, D. ; Shi, Y. ; Banati, R. B. ; Liu, G.-J. ; Middleton, R. J. ; Mitteregger-Kretzschmar, G. ; Perneczky, R. ; Koeglsperger, T. ; Neher, J. J. ; Tahirovic, S. ; Brendel, M.DKFZ* ; Herms, J. ; Paeger, L.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-62500-8

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.

Keyword(s): Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: physiopathology (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: diagnostic imaging (MeSH) ; Alzheimer Disease: complications (MeSH) ; Locus Coeruleus: pathology (MeSH) ; Locus Coeruleus: metabolism (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Axons: pathology (MeSH) ; Axons: metabolism (MeSH) ; Olfactory Bulb: pathology (MeSH) ; Olfactory Bulb: metabolism (MeSH) ; Olfactory Bulb: physiopathology (MeSH) ; Mice (MeSH) ; Male (MeSH) ; Disease Models, Animal (MeSH) ; Female (MeSH) ; Mice, Transgenic (MeSH) ; Microglia: metabolism (MeSH) ; Microglia: pathology (MeSH) ; Norepinephrine: metabolism (MeSH) ; Aged (MeSH) ; Phagocytosis (MeSH) ; Adrenergic Neurons: pathology (MeSH) ; Adrenergic Neurons: metabolism (MeSH) ; Olfaction Disorders: pathology (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Smell: physiology (MeSH) ; Aged, 80 and over (MeSH) ; Mice, Inbred C57BL (MeSH) ; Plaque, Amyloid: pathology (MeSH) ; Norepinephrine ; Amyloid beta-Protein Precursor

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Contributing Institute(s):

1. DKTK Koordinierungsstelle München (MU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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