Verubecestat is a BACE1 protein inhibitor that can prevent amyloid beta (Aβ) production and aggregation as found in Alzheimer’s disease. Development of treatments using BACE inhibitors have failed because of unacceptable level of side-effects. However, most of the clinical trials have focused on the late-stage disease, rather than prevention. But while inhibition of BACE prevents the formation of Aβ aggregates, it does not effectively break up already existing aggregates. Therefore, this kind of treatment may be more effective in the early stages of Alzheimer’s.
Mouse Modeling of Alzheimer’s
A recent study used a 5XFAD mouse model, a well-developed model of Alzheimer’s pathology, which develops significant Aβ plaque formation. Before the onset of symptoms, the mice were fed with a diet containing verubecestat for 3 months, while symptoms were expected to be increasing.
The results in the 5XFAD model were good. The free Aβ found in the plasma was reduced, and therefore not available to begin forming aggregates. This treatment was shown to be dose-dependent. The higher-dosed animals still experienced the negative side-effects. By carefully developing a dosing regimen, it may be possible to treat the disease while also avoiding the side-effects.
Developing a Better Mouse Model
One problem when using a mouse model to study this disease is that the physiological effects may be over-exaggerated. That makes it difficult to determine whether a treatment may or may not actually be effective against the real disease. Another recent study attempted to address this issue by developing more specific mouse models. Therefore, an App knock-in model was developed, AppG-F, which is a closer resemblance to the disease’s pathophysiology seen in humans.
Treatment of the AppG-F mice with verubecestat significantly reduced the Aβ, much more effectively than with previous mouse models. Therefore a lower dose may successfully inhibit the disease development while causing less side-effects than previously experienced with larger doses. This new model is more compatible with studies focusing on BACE inhibitors.
Change of Strategy
Alzheimer’s disease is the most common form of dementia. There are no treatments to reverse the effects yet, and developing a preventive treatment may be a more effective strategy for this particular disease. Verubecestat is just one of many BACE inhibitors that are worth investigating further.
Oblak A, Cope Z, Quinney S, et al. Prophylactic evaluation of verubecestat on disease-and symptom-modifying effects in 5XFAD mice. Alzheimers Dement (N Y). 2022 Jul 14;8(1):e12317. doi: 10.1002/trc2.12317. PMID: 35846156
Watamura N, Sato K, Shiihashi G, et al. An isogenic panel of App knock-in mouse models: profiling β-secretase inhibition and endosomal abnormalities. Sci Adv. 2022 Jun 10;8(23):eabm6155. doi: 10.1126/sciadv.abm6155. PMID: 35675411