Does oxybutynin alter plaques, amyloid beta peptides and behavior in a mouse model of Alzheimer's disease?
OBJECTIVE
In elderly patients oxybutynin (Sigma-Aldrich) is commonly used to treat overactive bladder despite increased prevalence of Alzheimer's disease in this population. We determined whether oxybutynin altered plaque formation, amyloid beta peptide expression and behavior in a transgenic mouse model of Alzheimer's disease expressing the mutant human presenilin 1 (deltaE9) and a chimeric mouse/human amyloid precursor protein (APPswe).


METHODS
Mice were treated for 30 days in an acute experiment or 5 months in a chronic experiment with oxybutynin (30 mg/kg) or vehicle. Behavioral testing was performed monthly with the elevated plus maze (Med Associates, St. Albans, Vermont) in the chronic experiment. Brains were tested for plaque burden using Hirano silver and thioflavin-S (Sigma-Aldrich) staining. Amyloid beta peptide expression was tested using enzyme-linked immunosorbent assay for amyloid beta peptides 1-40 and 1-42.


RESULTS
Animals treated with chronic oxybutynin had a decreased plaque burden in the hippocampus (mean +/- SEM 2.2 +/- 0.4 vs 4.1 +/- 0.9 plaques, p <0.05) and cortex (5.8 +/- 0.7 vs 11.6 +/- 2.1, p <0.05) compared to animals treated with vehicle. Oxybutynin treated animals also had decreased expression of amyloid beta 1-42 (82.8 +/- 9.0 etag/ml vs 105.6 +/- 5.5 etag/ml, p = 0.05) compared to animals treated with vehicle. Female Alzheimer's disease mice treated with oxybutynin but not males showed improved behavior with a greater percent of time spent in the closed arm or elevated plus maze (95.9% +/- 1.6% vs 35.6% +/- 18.9%, p <0.05). The greatest difference was noted at 3 months of treatment compared to vehicle.


CONCLUSIONS
These results suggest that oxybutynin may slow the progression of Alzheimer's disease in this model.
Klausner
Adam P
AP
Department of Neuroscience, University of Virginia Health System, Charlottesville, Virginia, USA. apklausner@vcu.edu
Sharma
Seema
S
Fletcher
Sophie
S
Neff
Pamela
P
Yang
Sang-Kuk
SK
Son
Hwancheol
H
Tuttle
Jeremy B
JB
Steers
William D
WD
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001519:Behavior / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002678:Chimera; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D018727:Muscarinic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D053764:Presenilin-1; C005419:oxybutynin