Pregabalin treatment does not affect amyloid pathology in 5xfad mice

Katherine R. Sadleir*, Jelena Popovoic, Wei Zhu, Cory T. Reidel, Ha Do, Richard B. Silver-Man, Robert Vassar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background: Calcium dysregulation has been proposed to play a causative role in the development of Alzheimer’s disease pathology. Pregabalin is a compound already approved for human use, marketed as the prescription drug Lyrica. It binds the α2-δ subunit of P/Q-type voltage-gated calcium channels, lowering calcium influx and providing effective treatment for epilepsy and neuropathic pain. Objective: We hypothesize that increased resting calcium in neuronal processes near amyloid plaques plays a role in the development of neuritic dystrophies and further progression of amyloid pathology. Methods: 5XFAD mice were treated orally for 12 weeks with pregabalin, then immunoblotting and immunofluorescent imaging were used to quantify neuritic dystrophy and amyloid deposition in pregabalin compared to placebo-treated mice. Results: The treatment did not decrease markers of neuritic dystrophy or amyloid deposition. The image analysis of neuritic dystrophy on a plaque-by-plaque basis showed a small non-significant increase in the relative proportion of LAMP1 to Aβ42 in plaques with areas of 50-450 μm2 in the cortex of pregabalin-treated mice. In addition, there was a statistically significant positive correlation between the measured cerebral concentration of pregabalin and the relative levels of BACE1 and Aβ in the cortex. This relationship was not observed in the hippocampus, and there was no increase in average Aβ levels in pregabalin treated mice compared to placebo. We confirmed previous findings that smaller amyloid plaques are associated with a greater degree of neuritic dystrophy. Conclusion: Pregabalin may have an effect on Aβ that merits further investigation, but our study does not suggest that pregabalin contributes substantially to amyloid pathology.

Original languageEnglish (US)
Pages (from-to)283-297
Number of pages15
JournalCurrent Alzheimer Research
Volume18
Issue number4
DOIs
StatePublished - 2021

Keywords

  • 5XFAD
  • Alzheimer’s
  • Amyloid
  • BACE1
  • Calcium
  • Dystrophic neurites
  • Pregabalin
  • Synthesis

ASJC Scopus subject areas

  • General Medicine

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