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<p>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 <i>App</i><sup><i>NL-G-F</i></sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月8日

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  • 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,
  • Lars Paeger

摘要

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.