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

Unpublished

Bibliographic

Year of Publication:
2021
Contact PI Name:
Stacey J Sukoff Rizzo
Contact PI Affiliation:
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Co-Authors:
AL Oblak, ZA Cope, SK Quinney, R Pandey, C Biesdorf, AR Masters, KD Onos, L Haynes, KJ Keezer, JA Meyer, J Peters, SC Persohn, AA Bedwell, K Eldridge, R Speedy, G Little, S-P Williams, M Sasner, G Howell, G Carter, H Williams, BT Lamb, PR Territo
Primary Reference (DOI):
Conflict of Interest:
Dr. Lamb has served as a consultant for AvroBio and Eli-Lilly
Study Goal and Principal Findings (Abstract):
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 NIA resources of the MODEL-AD Preclinical Testing Core (PTC) Drug Screening Pipeline. 5XFAD mice were administered verubecestat ad libitum in chow from 3-6 months of age, prior to the onset of significant disease pathology. Following treatment, in vivo imaging was conducted with 18F-AV45 and 18-FDG-PET/MRI, brain and plasma beta-amyloid (Aβ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with pharmacokinetic data. 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.  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.
Funding Source:
National Institutes of Health (NIH)
National Institute on Aging (NIA)

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Verubecestat
Therapeutic Target:
BACE1

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1
Strain/Genetic Background:
C57BL/6J

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Key Biological and/or Chemical Resources

Antibodies
Provider (Company, Manufacturer, Individual, Laboratory):
Ionized Calcium Binding Adaptor Molecule 1 (Iba1)
Wako
ABC-HRP (Secondary Antibody)
Vector Labs
Thioflavin S
Sigma-Aldrich
Assays
Provider (Company, Manufacturer, Individual, Laboratory):
4G8 ELISA
MesoScale Discovery
BCA Protein Assay
Pierce
HPLC-MS/MS (Pharmacokinetics)
IU CPAC
NanoString Mouse AD Panel
Nanostring
MagMax mirVANA Total RNA Isolation Kit
Thermo Fisher
Total RNA Nano Assay
Agilent
King Fisher Flex Purification System
Thermo Fisher
PET/MRI
Indiana University Radiology Department
Chemicals
Provider (Company, Manufacturer, Individual, Laboratory):
Double Distilled Water (ddH2O)
Laboratory of Stacey Rizzo
PBS
Sigma
Tween 20
Sigma
Formic Acid
Sigma-Aldrich
T-Per
Thermo Scientific
Verubecestat
Selleck Chemicals
MK-2206
Selleck Chemicals
Methyl Tertiary Butyl Ether (HPLC Grade)
Fisher Scientific
Methanol (Optima LC-MS Grade)
Fisher Scientific
Acetonitrile (Optima LC-MS Grade)
Fisher Scientific
Deionized Water (Purified)
IU CPAC
Trizol
Thermo Fisher
Phosphatase Inhibitors
Sigma-Aldrich
Diethylamine (DEA)
Sigma-Aldrich
Protease Inhibitors
Sigma-Aldrich
NaCl
Sigma-Aldrich
Tris
Thermo Fisher
Sodium Phosphate Dibasic
VWR
Sodium Azide
Thermo Fisher
Sucrose
Thermo Fisher
EDTA
Thermo Fisher
EGTA
Thermo Fisher
[18F]AV-45
PetNet Indiana
[18F]FDG-PET
PetNet Indiana
Software and Algorithms
Provider (Company, Manufacturer, Individual, Laboratory):
nSolver
Nanostring
R 3.4.3
The R Project
Graphpad
Prism
Algorithms: Custom Analysis (PMID 33172468)
Laboratory of Greg Carter
Softmax Pro
Spectramax
Ethovision
Noldus
Accuscan
Omnitech
Singo (MRI Acquisition)
Siemens
IndyPET3 (PET Acquisition)
Indiana University Radiology Department
IDL (Software Development)
ITT Solutions
Analyze (PET/MRI Analysis)
AnalyzeDirect
MCID (Autoradiography/IHC Analysis)
InterFocus
Excel
Microsoft
R (Stats)
R Core Team
RStudio
RStudio Team
SPSS
IBM 1.0.0.1406
deSolve
R v3.4.3
Scitex 5500 TRAP Analyis v 1.6.2
IU CPAC

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Exploratory Activity
Frailty Index
Open Field Test
Spontaneous Alternation
Motor Function
Locomotor Activity
Path Length
Rotarod Test
Thigmotaxis
Histopathology
Activated Microglia
beta Amyloid Deposits
Biochemical
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
Brain-Formic Acid Soluble beta Amyloid Peptide 40
Brain-Formic Acid Soluble beta Amyloid Peptide 42
Immunochemistry
Ionized Calcium Binding Adaptor Molecule 1 (Iba1)
Spectroscopy
Mass Spectrometry
Imaging
[18F]AV45-PET
[18F]FDG-PET
Magnetic Resonance Imaging (MRI)
Standardized Uptake Value Ratio (SUVR)
Biomarker
Plasma-beta Amyloid Peptide 42
Plasma-beta Amyloid Peptide 40
Pharmacokinetics
Brain/Plasma Ratio
Clearance (L/h/kg)
Cmax
Drug Concentration-Plasma
Drug Concentration-Brain
PK/PD Modeling
t1/2 (Elimination Half-Life)
Tmax
Volume of Distribution (V)
Pharmacodynamics
Target Engagement (Reduction beta Amyloid Peptide 40-Brain)
Target Engagement (Reduction beta Amyloid Peptide 42-Brain)
Target Engagement (Reduction beta Amyloid Peptide 40-Plasma)
Target Engagement (Reduction beta Amyloid Peptide 42-Plasma)
Toxicology
Body Weight
Coat Color Change
General Behavior
Physical Appearance
Omics
Gene Expression Profile-Alzheimer's-Related Genes