Acitretin reverses early functional network degradation in a mouse model of familial Alzheimer’s disease

Eduardo Rosales Jubal*, Miriam Schwalm, Malena dos Santos Guilherme, Florian Schuck, Sven Reinhardt, Amanda Tose, Zeke Barger, Mona K. Roesler, Nicolas Ruffini, Anna Wierczeiko, Michael J. Schmeisser, Ulrich Schmitt, Kristina Endres, Albrecht Stroh

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Aberrant activity of local functional networks underlies memory and cognition deficits in Alzheimer’s disease (AD). Hyperactivity was observed in microcircuits of mice AD-models showing plaques, and also recently in early stage AD mutants prior to amyloid deposition. However, early functional effects of AD on cortical microcircuits remain unresolved. Using two-photon calcium imaging, we found altered temporal distributions (burstiness) in the spontaneous activity of layer II/III visual cortex neurons, in a mouse model of familial Alzheimer’s disease (5xFAD), before plaque formation. Graph theory (GT) measures revealed a distinct network topology of 5xFAD microcircuits, as compared to healthy controls, suggesting degradation of parameters related to network robustness. After treatment with acitretin, we observed a re-balancing of those network measures in 5xFAD mice; particularly in the mean degree distribution, related to network development and resilience, and post-treatment values resembled those of age-matched controls. Further, behavioral deficits, and the increase of excitatory synapse numbers in layer II/III were reversed after treatment. GT is widely applied for whole-brain network analysis in human neuroimaging, we here demonstrate the translational value of GT as a multi-level tool, to probe networks at different levels in order to assess treatments, explore mechanisms, and contribute to early diagnosis.

Original languageEnglish
Article number6649
Pages (from-to)6649
JournalScientific Reports
Volume11
Issue number1
DOIs
Publication statusPublished - 23 Mar 2021

Keywords

  • Acitretin/pharmacology
  • Alzheimer Disease/diagnostic imaging
  • Amyloid beta-Peptides/metabolism
  • Animals
  • Brain/drug effects
  • Brain Waves
  • Calcium/metabolism
  • Disease Models, Animal
  • Humans
  • Immunohistochemistry
  • Mice
  • Neural Pathways/drug effects
  • Neurons/drug effects
  • Optical Imaging
  • Plaque, Amyloid/metabolism
  • Protein Aggregation, Pathological
  • Synapses/drug effects

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