Early Locus Coeruleus noradrenergic axon loss drives olfactory dysfunction in Alzheimer’s disease
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 App NL-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.
Article Details
Authors (30)
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
Biomedical Center, Biochemistry, Faculty of Medicine, Ludwig-Maximilians-Universität München
Sabina Tahirovic
Matthias Brendel
Jochen Herms
Lars Paeger