Details

Autor(en) / Beteiligte

• Oblak, Adrian L.
• Cope, Zackary A.
• Quinney, Sara K.
• Pandey, Ravi S.
• Biesdorf, Carla
• Masters, Andi R.
• Onos, Kristen D.
• Haynes, Leslie
• Keezer, Kelly J.
• Meyer, Jill A.
• Peters, Jonathan S.
• Persohn, Scott A.
• Bedwell, Amanda A.
• Eldridge, Kierra
• Speedy, Rachael
• Little, Gabriela
• Williams, Sean‐Paul
• Noarbe, Brenda
• Obenaus, Andre
• Sasner, Michael
• Howell, Gareth R.
• Carter, Gregory W.
• Williams, Harriet
• Lamb, Bruce T.
• Territo, Paul R.
• Sukoff Rizzo, Stacey J.

Titel

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

Ist Teil von

• Alzheimer's & dementia : translational research & clinical interventions, 2022, Vol.8 (1), p.e12317-n/a

Ort / Verlag

Hoboken: John Wiley & Sons, Inc

Erscheinungsjahr

2022

Quelle

Wiley Online Library

Beschreibungen/Notizen

• 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.