P2-064: novel model for evaluating the effects of bace inhibitor candidates on synaptic function and aβ levels in mouse brain

β-Secretase cleaving enzyme 1 (BACE1) inhibition is a prime therapeutic drug target for blocking the initiation of pathogenic amyloid cascade associated with Alzheimer's disease (AD). BACE inhibitors reduce CSF Aβ from pre-dosing levels in human subjects. Furthermore, BACE1 play a physiological role on synaptic formation and function in preclinical/pharmacological studies. Development of an effective BACE inhibitor has been challenging and results to date have been mixed. Researchers would benefit from a preclinical model that could inform whether new BACE inhibitor candidates are worth further development. This model utilizes data from C57BL/6 mice experiments to evaluate a novel BACE inhibitor (NBI) versus a known reference BACE inhibitor (RBI). Specifically, mice were treated orally once-daily for 4 weeks. After the treatment was complete, measurements of dendritic spine density in the cortical slice with Golgi method and mitochondrial function (oxygen consumption rate) in hippocampal synaptosomes fraction by extracellular flux analyser were evaluated. The brain and CSF samples and the Aβ concentrations in the samples were measured by Aβ ELISA in order to compare these observed effective doses among spine density, mitochondrial function, and reduction of Aβ. In our model experiments, we were able to demonstrate that our NBI did not affect the spine density in the mouse cortical layer or mitochondrial function in hippocampal synaptosomes, but significantly reduced mouse CSF Aβ levels following 4-week treatment at 10 mg/kg. After 4-week treatment at 30 mg/kg, the NBI decreased spine and mitochondrial function, whereas the RBI decreased spine and mitochondrial function at the effective doses for reducing Aβ in mice. Our model demonstrated the ability to detect a lack of synapse impairment for a NBI at a dose that resulted in CSF Aβ-reduction in the mouse, in contrast to the RBI, indicating this approach may be helpful for estimating pharmacological risk-benefit among novel BACE inhibitors.