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Basic Science and Pathogenesis.

Holly C Hunsberger1,2, Kameron Kaplan1, Lainey B Toennies1

  • 1Rosalind Franklin University, North Chicago, IL, USA.

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Anxiety exacerbates Alzheimer's disease (AD) progression in females, impacting hippocampal pathways. Benzodiazepines may worsen memory, while menopause-induced anxiety shows potential brain compensation.

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Area of Science:

  • Neuroscience
  • Gerontology
  • Pharmacology

Background:

  • Preliminary studies in female Alzheimer's disease (APP/PS1) mice indicated earlier anxiety and cognitive decline linked to unbalanced brain networks.
  • Human analysis of the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset confirmed higher anxiety in female AD subjects, faster dementia transition in females with amyloid deposition, smaller brain volumes in anxious females, and anxiety as a key predictor of dementia transition.

Purpose of the Study:

  • To investigate the impact of anxiolytic treatment on Alzheimer's disease (AD) pathology in mice.
  • To dissect the neural circuitry underlying anxiety.
  • To determine if menopause accelerates AD pathology.

Main Methods:

  • Administration of alprazolam (Xanax) before a fear memory task in control and AD mice to measure hippocampal neuronal activation.
  • Injection of Cholera Toxin B into the amygdala and lateral hypothalamus to map projections to the ventral hippocampus in control and AD mice.
  • Induction of menopause using VCD to assess anxiety-like behavior and memory function.

Main Results:

  • Alprazolam treatment decreased memory retention in male and female mice, potentially due to reduced ventral hippocampus retrieval cell activation.
  • Perimenopausal mice exhibited earlier anxiety-like behavior and cognitive decline, with a rebound in postmenopause suggesting compensatory mechanisms.
  • Increased projections in the ventral hippocampus are predicted in female AD mice compared to controls and males.

Conclusions:

  • Neuropsychiatric symptoms influence cognitive decline via sex-specific hippocampal pathways.
  • Benzodiazepines may not be beneficial for Alzheimer's disease patients.
  • Menopause can trigger anxiety phenotypes, but the brain may possess compensatory mechanisms for hormonal changes.