A new tool for studying Alzheimer`s disease

Imaging and tracking a key player in the disease made possible by a new marker

July 26, 2018

Because of its frequent occurrence and socio-economic relevance, Alzheimer’s disease is a major subject of biomedical research, and many pieces of the puzzle of its origin are already in place. However, methods for tackling certain important unsolved questions about the molecular basis of the disease are still missing in the researchers’ toolbox. Scientists at the Max Planck Institute for Medical Research and Friedrich-Alexander University Erlangen-Nuremberg have now developed a tool for studying one of the key players involved in the disease. This new marker allows tracking and imaging of the enzyme BACE1 without requiring antibodies or genetic manipulation. The marker could be valuable in the development of new therapies.

Alzheimer’s disease (AD) is the most common form of dementia causes memory decline and cognitive impairments. Given the aging population, it is expected to become a growing socio-economic challenge in the coming decades. There is no known cure for the disease. One major characteristic is the appearance of so-called amyloid plaques in patients’ brains. Plaques mainly consist of amyloid beta peptides. Those originate from the amyloid precursor protein. The precursor protein is enzymatically cleaved to form the shorter amyloid beta peptides, which are toxic to neurons and accumulate to form the observable plaques. The rate-limiting enzyme in the amyloid beta production is beta-secretase 1 (BACE1). This makes BACE1 a key player in the development of AD.

Decades of research on BACE1 have already shed light on its function, localization and activity, but even with state-of-the-art methods, various details have remained enigmatic. A limiting factor is the lack of markers that allow imaging and tracking of BACE1 in living cells and tissues without hampering its native properties.  Imagine that you are flying over a crowd of people and want to pick out a certain person but it is raining and people are using huge umbrellas. Even though you might know the color of the person’s umbrella, you would never know exactly where the person is standing underneath it, who he or she is talking to or what he or she is doing. Similar problems arise in studying BACE1. So far, most markers developed for that purpose were simply too big. They shield the enzyme like an umbrella and make detailed resolution impossible.

“We have now developed a new marker, a small fluorogenic molecule that overcomes the drawbacks we have observed with other, bulky markers or genetically encoded labeling”, says Johannes Broichhagen, one of the authors and a scientist in the department of Chemical Biology led by Kai Johnsson. The molecule “simply” consists of a known inhibitor of the enzyme BACE1 linked to the dye SiR647, and hence is named SiR-BACE1. It is useable without further tags or modification. In essence, “it specifically marks BACE1 for fluorescent imaging, is easy to apply, and is compatible with a broad range of imaging systems”, says Sandra Karch, an author and BACE1 expert from the FAU Erlangen. A major advantage of the marker is its applicability in live cell imaging and nanoscopy.

This new tool could make a major contribution in studying AD and in developing new therapeutics. It could be especially valuable in finding ways of preventing interactions between BACE1 and the amyloid precursor protein to reduce the occurrence of plaques. Since it is based on a known inhibitor of BACE1, it could also play a role in the development of other inhibitors and in targeting them to the enzyme.

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