By Ella Nasser
We’re all familiar with Alzheimer’s disease and how terrible it can be, especially if it targets someone close to us, G-d forbid. And yet, despite the disease’s seriousness and prevalence, there are zero official, fool-proof cures. Scientists have been and continue to work off the “amyloid theory,” positing that an accumulation of amyloid-beta deposits in the brain is responsible for the disease. Even still, each breakthrough has come with its own set of drawbacks.
New models have been jump-started by the 2021 novel drug lecanemab/aducanumab, an antibody that actively dissolves the amyloid-beta plaques; however, this specific approach came with potential bleeding in the brain and low efficacy. All eyes now look towards y-secretase, an intramembrane enzyme that, in one way or another, seems to hold the key to AD’s cure. Y-secretase comprises four distinct parts that each play a role in cutting and generating the amyloid-beta fragments from a membrane-bound protein called APP (B-secretase is the second enzyme responsible for this cleaving process). Alzheimer’s relevant mutations have been proven to occur in the PS subunit of y-secretase, leading to the splicing of our problematic, 42 amino-acid long, amyloid-beta peptides.
At first, inhibition of the enzyme complex was the most promising method of minimizing amyloid accumulation. Unfortunately, this approach stirred up trouble since y-secretase is responsible for many other cellular functions and substrates besides AB42 (similar issues were found with using B-secretase inhibitors as well, although they may hold more therapeutic potential). Science now points to modulation of the y-secretase complex as the most promising approach, and small molecule drugs are currently in trial. These modulators are referred to as GSMs, and they work by binding to a side site on y-secretase to reduce the amount of AB42 chains produced. GSMs have gone through their own rollercoaster of discoveries and let-downs, resulting in different generations and versions. The most prominent small molecule candidate may be one that forces y-secretase to cut APP into smaller, unharmful fragments like AB37 and AB38.
There are also two additional drugs underway, one a molecule, and the other a peptide. Both take a somewhat different approach and target amyloid-beta oligomers (early clusters). The small molecule aims to prevent the oligomers from hardening into pesky plaque, and the short peptide works to fold them back into monomers.
Combining the different therapeutic techniques is a possibility that scientists have seriously considered as well. Additionally, due to a multitude of research and experimentation, there is now an increased knowledge of y-secretase’s molecular biology, which will only lead to further developments. Science also recognizes that more enhanced detection of AB42 deposits can curb Alzheimer’s before any symptoms or progression, especially when compounded with the new drugs. Early detection can perhaps take the form of blood tests or spectrometry-based methods because the current amyloid-beta levels incur high costs and complicated procedures.
Nevertheless, one thing is certainly clear: a promising future awaits in the fight against Alzheimer’s disease.