As the sixth leading cause of death in the United States, Alzheimers affects approximately five million adults and is estimated to cost the country $200 billion this year in terms of direct medical fees and other costs associated with caregivers and therapies. Since the first records of the disease by Alois Alzheimer in 1906, Alzheimers disease (AD) has become increasingly prevalent in our worldwide population, and scientists have been struggling for decades in efforts to figure out the causation of the disease and, most importantly, how to treat it. Having worked in laboratories that dedicate their work to studying neurodegenerative diseases, Ive realized that there is an immense amount of technology, effort and time that has been put into finding just one more small piece to this puzzle even a breakthrough in discovering the involvement of a protein in a disease, or how a specific mutation can contribute to its exacerbation, is an encouragement in the scientific field.

There are two essential cortical biomarkers of AD plaques, which are formed of beta-amyloid protein deposits, and tangles, comprised of the tau protein that builds up inside of cells. Current therapies have been targeting the aggregation of these proteins in hopes of detangling the deposits, as plaques and tangles contribute to massive cell and nerve death that lead to rapid cognitive decline, an inevitable symptom of AD.

The mechanism of protein accumulation is important to understand for researchers to determine the cause of buildup. Beta-amyloid (A) plaque fragments are a result of a cleavage reaction of the amyloid precursor protein (APP), a membrane protein that is found in neuronal synapses. Through post-translational modifications, APP can be separated into many different sections based on proteases and their specific cleavage sites (Fig. 1). Normally, the -secretase protease cleaves APP in the non-amyloidogenic pathway and the protein is rendered functional for other cellular tasks. However, when -secretase comes across APP and severs the protein at another site, it leaves open the sequence correlated to -secretase, the third enzyme that can come in and cleave APP. The result of these two cleavages is A.

Concerted efforts have been made to block the - and -secretase cleavage sites, and pharmaceutical companies are currently testing drugs for their efficacy in slowing down the rate of AD progression. However, researchers have questioned this direction, citing that these trials have been inconclusive or failed to control A formation.

What is particularly fascinating about this pathway is that perhaps our genetics unknowingly held part of the answer all along. In a recent finding published in Nature by a research team from DeCode Genetics based in Iceland, a rare gene mutation on APP was found to be protective against AD. This is the first mutation of its kind to be neuroprotective, as many other mutations of APP have exacerbated the AD phenotype. Whole genome sequencing of approximately 1800 Icelanders resulted in the discovery of this variant and researchers proved that it decreased the formation of A and protein aggregation by 40 percent. The single point mutation was present in slightly less than one percent of the Icelanders and statistical analysis shows that carriers of the variant were about twice as likely to reach the age of 85 than non-carriers. In addition, cognitive function of carriers in the age range of 80-100 was vastly improved in comparison to their counterparts.

As exciting as this finding is, we must keep in mind that only a small subset of Icelanders carries the protective variant and that the study should be extended to other populations for a broader analysis. Whole genome sequencing is also a relatively expensive effort that is not just a simple blood test at the doctors office, and you would need to conduct a specific test at a laboratory or genetics company to tell if you have the mutation. Another interesting fact is that carriers of the gene mutation also reap its protective advantages though this scientific discovery has proven that researchers are on the right track for targeting APP and preventing A formation in gene therapies, perhaps preventing APP cleavage entirely is unnecessary and only a partial reduction is needed for a therapeutic benefit.

There will always be caveats and exceptions to any scientific discovery, but the overall enthusiasm for this new insight has been greatly encouraging to the research community. With the increase of resources, technology and dedication to biomedical research in the past decade, I am positive that we will be able to step forward in our advancements to understand and develop therapies for those affected by neurodegenerative diseases.

Debbie Tseng is a second year Ph.D. candidate at Weill Cornell Medical College. She may be reached at dgt2001@med.cornell.edu. Whats Up, Doc? appears alternate Fridays this semester.

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One Small Gene Mutation Leads to One Giant Leap for Alzheimer’s Research

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