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Basic Science and Pathogenesis.

Derya Sargin1

  • 1University of Calgary, Calgary, AB, Canada.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 23, 2025
PubMed
Summary

Early tau pathology in serotonin neurons of the dorsal raphe nucleus causes anxiety, social behavior changes, and cognitive issues in Alzheimer's disease (AD). This mouse model reveals potential therapeutic targets for AD neuropsychiatric symptoms.

Area of Science:

  • Neuroscience
  • Alzheimer's Disease Research
  • Serotonin Neuron Function

Background:

  • Serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) are vital for socioemotional regulation and cognition.
  • These neurons are among the earliest affected by tau pathology in Alzheimer's disease (AD).
  • Neuropsychiatric symptoms are common early manifestations of AD.

Purpose of the Study:

  • To develop a mouse model investigating the impact of early tau pathology in DRN 5-HT neurons.
  • To understand how this specific pathology contributes to early AD-related neuropsychiatric symptoms.
  • To identify molecular mechanisms underlying these behavioral changes.

Main Methods:

  • Generated a cre-dependent adeno-associated virus (AAV) to express human tau (hTauP301L) specifically in DRN 5-HT neurons of Pet1-cre mice.

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  • Assessed socioemotional and cognitive behaviors using a battery of tests four weeks post-infusion.
  • Utilized RNA-sequencing (RNA-seq) to explore underlying molecular changes.

    • Main Results:

    • Pathological tau in 5-HT neurons led to increased anxiety-like behavior and altered stress coping.
    • Observed sex-specific social behavior abnormalities (in females) and mild cognitive impairment.
    • Identified molecular markers associated with early tau-induced behavioral alterations.

    Conclusions:

    • Early tau pathology in DRN 5-HT neurons contributes to key neuropsychiatric symptoms in AD.
    • Provides mechanistic insights into the onset of these symptoms.
    • Highlights potential therapeutic targets for early AD intervention.