β-secretase 1 (BACE1) was discovered to initiate the cleavage of amyloid precursor protein (APP) at the β-secretase site. Only after this cleavage does γ-secretase further cleave the BACE1-cleaved C-terminal APP fragment to release Aβ which is the potential cause of Alzheimer's disease (AD)[3]. Verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition[4].
Verubecestat/维罗司他 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
5XFAD mouse model
Oral
10, 30, and 100 mg/kg/day
From 3 to 6 months of age, lasting 3 months
To evaluate the prophylactic treatment effects of verubecestat in an AD mouse model, showing dose-dependent reductions in amyloid plaque deposition but no cognitive improvement and with side effects.
Alzheimers Dement (N Y). 2022 Jul 14;8(1):e12317
Mice
AppG-F and AppNL-G-F mouse models
Oral
10 mg/kg
Single dose, analyzed after 3 hours
To evaluate the inhibitory effect of Verubecestat on Aβ levels. Results showed that Verubecestat significantly reduced Aβ40 and Aβ42 levels in the cortices of AppG-F mice but not in AppNL-G-F mice.
Sci Adv. 2022 Jun 10;8(23):eabm6155
Mice
Wild-type mice
Oral gavage
3 mg/kg
Daily administration for 4 months
To evaluate the effects of Verubecestat on learning and synaptic plasticity. Results showed that Verubecestat significantly reduced hippocampal LTP and cognitive behaviors.
Mol Psychiatry. 2021 Nov;26(11):6394-6410
Mice
Tg2576-AβPPswe transgenic mice
Dietary administration
110 mg/kg/day
Continuous for 12 weeks
Verubecestat significantly suppressed the accumulation of total levels of brain Aβ40 and Aβ42 and Thioflavin S positive plaque load. Compared to controls, verubecestat-treated mice showed significantly reduced plaque load in the cortex and hippocampus without significantly increasing ARIA-H events.
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