Breaking Down β-Amyloid Protein: Removal of BACE1 in a Mouse Model

Author: Andrew Rice

The paper described below can be found here:

Within the last week, Hu et. al. published a paper in the Journal of Experimental Medicine that has been plastered all across the internet as a way to “reverse Alzheimer’s”. Alzheimer’s disease (AD) is the sixth leading cause of death in the United States./ The disease is characterized by neuroinflammation and a consistent decline in cognitive function, leading to dementia and neurodegeneration. AD is also a disease with a complex, mysterious pathology. However, two theories regarding the disease are currently prevailing. The β-amyloid hypothesis believes that the buildup of misfolded β-amyloid proteins in the brain that form deleterious plaques, a hallmark of AD, is the primary cause of the disease. Normally, β-amyloid proteins play an important role in the growth and repair of neurons, but when these proteins misfold, they accumulate and interfere with neuronal functioning. The tau hypothesis believes that the hyperphosphorylation of tau proteins is the primary cause of AD.1 While both of these hypothesis describe symptoms of AD, the disease can also be characterized by both neuroinflammation and neurodegeneration, culminating physiologically in memory loss and later dementia.

Hu et. al. have recognized the importance of understanding the disease pathology in treating this disease, and to do so they have observed the results of gradually deleting the BACE1 gene in mice. β-site amyloid precursor protein (APP)–cleaving enzyme 1, or BACE1, is a protein that is critical in the formation of β-amyloid. BACE1 cleaves amyloid precursor protein (APP) to yield a C-terminal fragment anchored to the membrane which is further cleaved to yield β-amyloid protein.2

The group began by generating BACE1 conditional knockout mice. They targeted the exons directly in front of and behind the gene. By jumping through a few genetic hoops, the group succeeded in breeding mice that began to express the BACE1 gene less and less as they aged, dubbed the BACE1fl/fl/UbcCreER mice. These mice expressed minimal amounts of BACE1 by around 80-90 days after birth. They later crossed these mice with 5xFAD mice, which have been bred to develop amyloid plaques at approximately 75 days after being born. This is where the paper become critically important. As the BACE1fl/fl/UbcCreER/5xFAD mice aged, they saw an increase in neural plaque formation, but these plaques were completely removed as they kept aging and produced virtually zero BACE1. The control group, which was simply 5xFAD mice, suffered from neural degeneration and a severe quantity of amyloid plaques.

These BACE1 hybrid mice continued to impress. The amount of APP-C83 in the BACE1 mice was significantly lower than expected, and the authors aren’t quite sure why. They theorize that the removal of BACE1 in some way caused an improved lysosomal-autophagic function. If this is the case, such a system will be quite useful in treating AD patients in the future. It was shown that the BACE1fl/fl/UbcCreER/5xFAD mice reversed dystrophic neurites and gliosis, as well as partially reversed the loss in cognitive functioning associated with the buildup of amyloid plaques. These mice were even found to have improved learning when compared to their plaque-filler counterparts.
This study is extremely influential, and may be a precursor of much research to come. This study marks the first time that, through sequential alteration of an organism, neural β-amyloid plaques were completely reversed and degraded after forming. This screams target to drug companies. While they’ve been targeting BACE1 for quite some time, many drugs that target this enzyme have failed. This study may refuel that fire. By proving the slow deletion of BACE1 can reverse the formation of plaques (at least in a mouse model), the authors of this study have redefined this enzyme as a target. Because the rats also displayed cognitive benefits from this deletion, this study further supports the β-amyloid hypothesis rather than the tau hypothesis. Once scientists understand which of these mechanisms is causal in AD, they can begin developing methods to treat the disease.

It’s important to note that the complete removal of β-amyloid plaques from the mice was not without detriment, however. Removal of BACE1 has previously been associated with reduced neurogenesis, depression, hyperactivities, abnormal generation of astrocytes, and a decrease in myelination.2 It’s clear that simply removing the BACE1 enzyme in human models would not be without major problems. This study has been seen by news websites as groundbreaking, but for all the wrong reasons. The study does get us one step further to understanding the complex disease pathology of AD, but it has come nowhere close to finding a way to “reverse Alzheimer’s Disease”. The disease is also characterized by neuroinflammation and other issues that aren’t addressed by removal of BACE1. Many drugs targeting BACE1, such as verubecestat, have failed when they make it to clinical trials due, and some companies have completely given up on the idea of targeting this enzyme.3 Furthermore, removal of BACE1 brings with it an entirely new set of issues for the body to tackle in order to maintain homeostasis and recover. If we find a treatment for AD, it will likely need to be as complex as the disease pathology itself, consisting of at least one if not many multifunctional drugs that address the many issues with this disease state. Future work will inevitably explore the complex disease state further, using this paper as a landmark study.

Sources Cited:

1. Mohammad Khanahmadi, Dariush D. Fahrud, and Maryam Malmir. Genetic of Alzheimer’s Disease, A Narrative Review Article. Iran Journal of Public Health. 2015. Accessible from:
2. Das, Brati; Yan, Riqiang. Role of BACE1 in Alzheimer’s Synaptic Function. Translational Neurodegeneration. 2017. 6:23

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