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Research Updates in Psychiatry

Is BACE1 a Significant Alzheimer’s Disease Target?

Last year, neuroscience researchers at the Cleveland Clinic claimed to have reversed the neuropathology as well as the cognitive and memory decline associated with Alzheimer’s Disease (AD) in a mouse model. The target was the β-secretase protein, also called the β-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1).

BACE1 is an aspartyl protease which, as its name suggests, is responsible for the cleavage of the amyloid precursor protein (APP), a major step within an intricate cascade leading to the formation of beta-amyloid plaques, protein aggregates which manifest in patients with AD (Hu et al., 2018). Therefore, the rationale behind the Cleveland Clinic study was to inhibit BACE1, as a means of stymying plaque formation at a key, initial stage of the amyloid cascade.

Using the Cre-Lox recombination technique, the researchers generated mice lacking the gene for BACE1, mice which, ultimately, would not produce this enzyme. These BACE1-deficient mice were then bred with mice exhibiting amyloid-beta deposition in their brains within 75 days of life.

The resulting offspring mice were then assessed for AD pathology. While plaques were initially observed in the offspring mice, these plaques diminished as the offspring mice aged, and correspondingly lost BACE1 activity. After 300 days, amyloid-beta plaques were almost entirely eliminated.

Based on these results, this experiment appears to clearly corroborate the notion that inhibiting BACE1 in mice could (and does) have a marked effect on reversing and ameliorating the amyloid pathology associated with AD.

Beyond pathology, the observations of symptomatology in the mice used in the Cleveland Clinic study also give extra credence to BACE1 inhibition. In this experiment, loss of BACE1 function in mice  also improved the learning and memory of these mice with Alzheimer’s Disease, assessed via administering a contextual fear conditioning test.

The researchers placed the mice into a fear conditioning chamber, administering sounds and foot shocks. Freezing time was used as the rubric to gauge context-dependent fear learning. There was a statistically significant difference in freezing time between mice carrying the BACE1 deletion, and those carrying BACE1, with times notably higher in BACE1-deleted mice. This (result) indicates an enhanced level of fear learning in BACE1-deleted mice relative to their BACE1 exhibiting counterparts.

Targeting of BACE1 Faces Obstacles

Such significant improvements in amyloid-beta pathology and learning in mice would suggest that BACE1 inhibition is a potentially groundbreaking and vital therapeutic target for AD, would they not? Unfortunately, targeting BACE1 faces a plethora of obstacles and potential shortcomings.

Firstly, the major stumbling block is making the transition from an animal model to actual patients. This experiment was conducted in a mouse model, for which results do not guarantee successful results in human clinical trials. In fact, targeting BACE1 in human patients has actually been attempted before. Unfortunately, these trials have all proven to be unsuccessful thus far.

Verubecestat, a BACE1 inhibitor, was undergoing trials in patients with prodromal Alzheimer’s disease (AD). As it turned out, Merck discontinued the study at Phase 3, as the inhibitor failed to improve amyloid-beta pathology and clinical outcomes in actual patients (PharmaTimes, 2018).

dd to that the ever-present risk of off-site effects, such as liver toxicity, for which another BACE1 inhibitor, pioneered by Eli Lilly, had to be scrapped from further evaluation. Another major pharmaceutical company, Roche, also launched Phase 1 trials with another early-stage BACE1 inhibitor, RG7129, but development and further research of this compound have since been terminated. Liver toxicity was cited as a reason for discontinuing the research, but Roche is still yet to officially offer an explanation for its decision to end the RG7129 study (Nature, 2017).

Additionally, enzymes like BACE1 are often not confined to one biochemical pathway, but are linked to multiple biological processes. BACE1 has been found to play a pivotal role in myelination of axons in neurons (Hu et al., 2006).  In fact, the Cleveland Clinic researchers acquiesced with the notion that BACE1 may actually be vital in facilitating optimal synaptic activity and cognitive function. They indicated that mice with BACE1 deletion exhibited compromised neurogenesis, impaired axon growth, as well as diminished long-term potentiation (LTP). Therefore, completely inhibiting BACE1 could also present potentially deleterious consequences, including, but not exclusive to, the cognitive and memory declines which it was intended to improve.

Timing Could Be a Factor

Taking into account all of these shortcomings, it is easy to be skeptical towards BACE1 as a target. However, I believe that the  unsuccessful results in patients stem largely from an issue of the timing for implementing BACE1 inhibition rather than whether or not it is effective at all.

As of early-2018, there is research suggesting that BACE1 inhibition should be done before the presentation of AD symptoms. Researchers at the German Center for Neurodegenerative Diseases proposed that BACE1 proteolytic cleavage process, being the rate-limiting step in the amyloid-beta cascade, is best targeted as a pre-symptomatic treatment when initial amyloid plaques have formed, but before amyloid deposition has become saturated and widespread.

Treatment with the NB-360 BACE1 inhibitor at the early stages of amyloid production greatly stymied the subsequent growth and deposition of amyloid-beta in mice relative to a control. These results suggest that BACE1 is, in fact, a major target in terms of inhibiting amyloid-beta deposition.

Moreover, amyloid-beta pathology is found to manifest up to decades before clinical symptoms of AD, such as cognitive decline and memory impairment, present themselves (Herholz et al., 2013). This suggests that responding to early pathology is the most optimal means of preventing the acquisition of AD symptoms.

Putting these results together, my belief is that BACE1 needs to be inhibited not when symptoms present, but well before, when pathology is at its earliest phase of presentation. Knowing which patients to assess for these pathology is another issue. One place to start is to conduct PET-scans for amyloid-beta in patients with a family history and genetic predisposition for AD, and administering the BACE1 inhibition for those who start to exhibit amyloid-beta formation.

BACE1 inhibition could then minimize levels of amyloid-beta, which, when reduced by 40%, could minimize the risk of acquiring AD almost sevenfold (Messing et al., 2012).

Alzheimer’s Disease continues to be shrouded in mystery. Many schools of thought have been proposed, and many preclinical trials have yielded success in animal models. However, getting further in finding a therapeutic to ameliorate or prevent AD pathology and symptomatology in actual humans remains elusive to this day.

Regardless, BACE1 inhibition is far from a lost cause. I believe that targeting BACE1 needs to be done at the initial stages of amyloid-beta formation, well before the initial stages of AD symptoms. The next set of hurdles are finding a way to administer the BACE1 inhibitor without off-site toxicity, to facilitate inhibition while not compromising the aforementioned important functions of BACE1, and to enable efficient bioavailability (penetrating the blood-brain barrier).

Clearly, there are many obstacles still to overcome, but the consistent improvement in amyloid-beta levels in mice suggests that BACE1 still carries huge potential as a target in humans, and still deserves further consideration. Overcoming these challenges may just be what is needed for BACE1 inhibition to be another contribution to solving the AD mystery that is afflicting the lives of millions of geriatric patients worldwide.

References

Herholz, K., & Kobylecki, C. (2013). Faculty of 1000 evaluation for Amyloid β deposition,  neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: A prospective cohort study. F1000 – Post-publication Peer Review of the Biomedical Literature. doi:10.3410/f.717988744.793475383

Hu, X., Das, B., Hou, H., He, W., & Yan, R. (2018). BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. The Journal of Experimental Medicine. doi:10.1084/jem.20171831

Hu, X., Hicks, C. W., He, W., Wong, P., Macklin, W. B., Trapp, B. D., & Yan, R. (2006). Bace1 modulates myelination in the central and peripheral nervous system. Nature Neuroscience, 9(12), 1520-1525. doi:10.1038/nn1797

Messing, J. (2012). Faculty of 1000 evaluation for A mutation in APP protects against Alzheimers disease and age-related cognitive decline. F1000 – Post-publication Peer Review of the Biomedical Literature. doi:10.3410/f.717952387.793458845

Nature. (2017, March 1). BACE inhibitor bust in Alzheimer trial [Review]. Retrieved from https://www.nature.com/articles/nrd.2017.43

Peters, F., Salihoglu, H., Rodrigues, E., Herzog, E., Blume, T., Filser, S., . . . Herms, J. (2018). BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology. Acta Neuropathologica. doi:10.1007/s00401-017-1804-9

PharmaTimes. (2018, February 14). MSD’s verubecestat fails again in Alzheimer’s trial. Retrieved February 28, 2018, from http://www.pharmatimes.com/news/mercks_verubecestat_fails_again_in_alzheimers_trial_1221910

Small SA, Simoes-Spassov S, Mayeux R, Petsko GA. (2017).  Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer’s Disease. Trends Neurosci. Oct;40(10):592-602.

 

Is BACE1 a Significant Alzheimer’s Disease Target?


Racheed Mani, B.A.

Racheed Mani, B.A. is now pursuing a medical degree at the Stony Brook University School of Medicine. He previously received his bachelor’s degree in biochemistry and psychology at New York University, while also serving as a psychiatric clinical research assistant.

 

APA Reference
Mani, R. (2020). Is BACE1 a Significant Alzheimer’s Disease Target?. Psych Central. Retrieved on July 9, 2020, from https://pro.psychcentral.com/is-bace1-a-significant-alzheimers-disease-target/

 

Scientifically Reviewed
Last updated: 20 Jan 2020
Last reviewed: By John M. Grohol, Psy.D. on 20 Jan 2020
Published on PsychCentral.com. All rights reserved.