DOI: 10.1002/alz.077596 ISSN: 1552-5260

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

Elyse Watkins, Declan Gallagher, Shreya Mahesh, Myles Reed, Robert J. Vassar
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology

Abstract

Background

Small 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.

Method

PDAPP 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.

Result

Treatment with BACE inhibitor led to a dose dependent protection from amyloid plaque buildup. There were treatment‐dependent effects on behavior.

Conclusion

This study has implications for determining a potential safe and effective dose of BACE inhibitors in humans.

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