Prophylactic evaluation of verubecestat on disease- and symptom-modifying effects in 5XFAD mice.

Abstract

Introduction:

Alzheimer's disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under-investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late-Onset Alzheimer's Disease (MODEL-AD) Preclinical Testing Core (PTC) Drug Screening Pipeline.

Methods:

5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F-florbetapir (AV-45/Amyvid) (18F-AV45) and 18-FDG (fluorodeoxyglucose)-PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (Aβ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data.

Results:

Prophylactic verubecestat treatment resulted in dose- and region-dependent attenuations of 18F-AV45 uptake in male and female 5XFAD mice. Plasma Aβ40 and Aβ42 were also dose-dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F-FDG uptake.

Discussion:

Prophylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating Aβ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL-AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early-stage AD.

• Authors: Adrian L Oblak, Zackary A Cope, Sara K Quinney, Ravi S Pandey, Carla Biesdorf, Andi R Masters, Kristen D Onos, Leslie Haynes, Kelly J Keezer, Jill A Meyer, Jonathan S Peters, Scott A Persohn, Amanda A Bedwell, Kierra Eldridge, Rachael Speedy, Gabriela Little, Sean-Paul Williams, Brenda Noarbe, Andre Obenaus, Michael Sasner, Gareth R Howell, Gregory W Carter, Harriet Williams, Bruce T Lamb, Paul R Territo, Stacey J Sukoff Rizzo
• Journal: Alzheimer's & dementia (New York, N. Y.) (Alzheimers Dement (N Y)) Vol. 8 Issue 1 Pg. e12317 ( 2022) ISSN: 2352-8737 [Electronic] United States
• PMID: 35846156 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.