APP, PSEN1, PSEN2, and BACE1 Genes on the Pathogenesis of Alzheimer’s Disease and Inhibition Strategies

Aaron Wang | 25 August 2024

Background

Many abnormalities have been found in the brains of patients who had neurodegenerative diseases such as Alzheimer’s disease. One of the most notable abnormalities has been found on the cellular level, namely clusters of toxic proteins called beta-amyloid plaques (Aß). These plaques, as well as neurofibrillary tangles and tau tangles, have been the focus of research for an extremely long time with multiple treatments targeting those plaques. Although none of these treatments have really worked, and the underlying cause of Alzheimer’s disease is still unknown, it is still good to know about these proteins and how they play into the disease.

In a previous article, a basic analysis of the role of amyloid-beta (Aß) plaques and Tau protein tangles in the progression of Alzheimer's disease were explored. A solid understanding of the how proteins contribute to the disease is important because the article will focus on more of the causes of why these proteins came to be. Although some of combinations of letters and numbers such as PSEN1 may sound daunting, this article hopes to break it down and act as a gentler introduction into the inner workings of the disease.

What is APP?

Amyloid Precursor Proteins (APP), are proteins that have the potential to be broken down into Aß plaques that could damage the brain and have toxic effects on the cellular environment of the brain. Found wedged in the plasma membranes of cells, APP is a transmembrane protein that is found in neurons. APP play an important role in synapses, which are the connections between different neurons. Specifically, APP was observed to be vital in the structural integrity of the extension of the neurons (dendrites) as well as the proper functioning of those synaptic connections (Tyan et al. 2012). However, mutations in both APP and enzymes that help with function can cause the plaques that could prove harmful to the brain.

Harmful cleavage of APP

APP undergoes regular cleavage in cellular efforts to maintain homeostasis. The cleavage of APP occurs to produce beneficial fragments as well as molecules to work facilitate cell signaling (Hartmann, 2013). However, mutations can occur, in both APP and the enzymes that help cleave APP, that create plaques.

When APP is cleaved, there are usually two processes that occur: amyloidogenic and nonamyloidogenic pathways. In the nonamyloidogenic pathway, which is not harmful, cleavage begins with α-secretase, a type of enzyme, which produces sAPPα. sAPPα is harmless and soluble, meaning that it does not build up and create plaques. Furthermore, sAPPα is associated with increased electrical activity, which may end up having sAPPα playing a beneficial role in the brain. When the cleavage occurs, an 83 amino acid chain remains in the membrane called C83. Later on, ɣ-secretase processes C83 with no harmful effects (Chen et al. 2017).

On the other hand, the amyloidogenic pathway starts with ß-secretase, another enzyme produced by the BACE1 gene, beginning the cleaving. When ß-secretase makes the cut, a 99 amino chain (C99) is left. However, because the C99 offers a specific order that allows for the formation of Aß plaques, when ɣ-secretase cleaves C99, multiple Aß is produced and set free into the extracellular matrix, which allows for those insoluble proteins to build up (Chen et al. 2017). With BACE1, elevated levels were correlated to higher levels of plaques. Furthermore, mutations along the BACE1 gene can lead to the continued dysfunction of ß-secretase.

Some of those enzymes were subjected to mutations in genes, which could be an underlying cause for the formation of Aß plaques. Let’s explore these mutations.

Presenilin

Presenilin genes (PSEN) are genes that contain instructions and information to build proteins (enzymes) that are involved in the cleaving process. Specifically, PSEN1 and PSEN2 are important components in the ɣ-secretase process, and mutations could potentially speed and facilitate the pathogenesis of Alzheimer’s disease. PSEN1 and PSEN 2 are genes that provide the information to create presenilin-1 and presenilin-2 proteins through protein synthesis.

PSEN1

PSEN1 plays a critical role in the production of presenilin-1 proteins. Presenilin-1 proteins are important in its role in ɣ-secretase. Specifically, presenilin-1 is a subunit of the ɣ-secretase enzyme, with presenilin-1 carrying out the cleavage. However, when mutations occur within this gene, the presenilin-1 proteins are incorrectly produced which leads to abnormal cleavages and functions. Mutations accounted for 70% of Alzheimer’s cases and were found to play an integral role in the overproduction of Aß plaques (National Library of Medicine).

Furthermore, mutations in PSEN1 can play a role in the dysfunction in calcium metabolism (Bagaria, 2022), which could compound or exacerbate malfunctions that have to do with astrocyte regulation of calcium ion. Astrocyte and their influence with calcium balance in the brain is explored in a previous article that can be found on this site.

PSEN2

PSEN2 is notable in its role of processing Aß plaques. PSEN2 mutations can prove harmful, as it interrupts the processing of these plaques. Although relatively rare, accounting for 5% of cases, a mutation in PSEN2 creates a phenomenon where Aß is overproduced and is unable to be broken down, therefore causing aggregation and may contribute to Alzheimer’s disease (National Library of Medicine).

Inhibition strategies

Based on this research and information, treatments have been directed at those genes as well as enzymes to try to inhibit their function in order to slow down plaque build up. One such treatment that is being explored revolves around the selective inhibition of ɣ-secretase and the presenilin-1 protein. Because the inhibition of ɣ-secretase could prove detrimental to other functions, inhibition strategies aimed to focus at the PSEN1 gene, which is the subunit that does the cleaving. One of the better treatments in this approach was the usage of MRK-560. MRK-560 was found to bind to PSEN1 and not the other complexes of the enzymes, therefore producing a viable route to inhibit the specific complex that seemed to be causing the problem. (Serneels et al., 2023)

Inhibition strategies for BACE1 and the ß-secretase enzyme is also underway. In a study conducted on mice, the genetic deletion of BACE1 was able to decrease the rate of Aß production (Vassar, 2014). However, the mice also experienced side effects such as seizures and other issues, BACE1 deletion may also hurt humans as well. However, this acts as further confirmation that BACE1 is indeed involved in the Aß production, and it remains to be seen if there is any safe way to suppress Aß production without said side effects.

Conclusion

While progress has been made in understanding the roles of APP, PSEN1, PSEN2, and BACE1 in Alzheimer’s, effective and safe treatments requires more information and a nuanced approach to inhibit harmful pathways while preserving essential physiological functions. Continued research into these genetic and enzymatic processes will be important in developing therapies that can cure progression of Alzheimer’s disease.

Works Cited

Bagaria, Jaya et al. “Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene.” International journal of molecular sciences vol. 23,18 10970. 19 Sep. 2022, doi:10.3390/ijms231810970

Chen, Guofang, et. al. “Amyloid beta: structure, biology and structure-based therapeutic development.” Acta Pharmacol Sinica, Vol. 38, 2017, pp. 1205-1235, Nature, https://doi.org/10.1038/aps.2017.28.

Hartmann D. Functional Roles of APP Secretases. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6221/#

MedlinePlus. "PSEN1 gene: MedlinePlus Genetics." U.S. National Library of Medicine, National Institutes of Health, medlineplus.gov/genetics/gene/psen1/.

MedlinePlus. "PSEN2 gene: MedlinePlus Genetics." U.S. National Library of Medicine, National Institutes of Health, medlineplus.gov/genetics/gene/psen2/.

Serneels, Lutgarde et al. “Selective inhibitors of the PSEN1-gamma-secretase complex.” The Journal of biological chemistry vol. 299,6 (2023): 104794. doi:10.1016/j.jbc.2023.104794

Tyan, Sheue-Houy et al. “Amyloid precursor protein (APP) regulates synaptic structure and function.” Molecular and cellular neurosciences vol. 51,1-2 (2012): 43-52. doi:10.1016/j.mcn.2012.07.009

Vassar, R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alz Res Therapy 6, 89 (2014). https://doi.org/10.1186/s13195-014-0089-7