Pregabalin Treatment Does Not Affect Amyloid Pathology In 5xfad Mice

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 alpha 2-delta 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 A beta 42 in plaques with areas of 50-450 mu m(2) 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 A beta in the cortex. This relationship was not observed in the hippocampus, and there was no increase in average A beta 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 A beta that merits further investigation, but our study does not suggest that pregabalin contributes substantially to amyloid pathology.