Title:Pregabalin Treatment does not Affect Amyloid Pathology in 5XFAD Mice
Volume: 18
Issue: 4
Author(s): Katherine R. Sadleir*, Jelena Popovoic, Wei Zhu, Cory T. Reidel, Ha Do, Richard B. Silverman and Robert Vassar
Affiliation:
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611,United States
Keywords:
Alzheimer's, amyloid, pregabalin, synthesis, BACE1, dystrophic neurites, calcium, 5XFAD.
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 voltagegated
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.
