Behavioral, biochemical, and neuropathological outcomes in amyloid‐bearing mice treated long‐term with a range of doses of BACE inhibitor

Abstract

AbstractBackgroundSmall molecule BACE inhibitors, while promising for the treatment of AD, have been discontinued in clinical trials due to early and non‐progressive cognitive worsening. There is great interest in finding a dose of inhibitors that can protect from AD pathology while sparing cognitive issues. Furthermore, there is interest in determining which substrate(s) is mediating the cognitive worsening.MethodPDAPP mice, which express human APP that lack mutations affecting BACE cleavage, were treated with five doses of BACE inhibitor in their chow. Mice were treated from 8 months to 14 months, and Morris Water Maze, Novel Object Recognition, and Rotarod were performed immediately prior to the study’s completion. Cleavage of BACE substrates, including APP, Sez6, Sez6L, APLP1, CHL1, and others were assessed by western blot, and correlated with cognitive assessments. The extent of amyloid buildup during treatment was quantified.ResultTreatment with BACE inhibitor led to a dose dependent protection from amyloid plaque buildup. There were treatment‐dependent effects on behavior.ConclusionThis study has implications for determining a potential safe and effective dose of BACE inhibitors in humans.