by Jessica Cao
Every 65 seconds, someone in the United States develops Alzheimer’s disease [1]. Alzheimer’s disease is the most common form of dementia, a general disease marked by a decline in cognitive function severe enough to interfere with daily function. Alzheimer’s in particular is characterized by cognitive impairment and memory loss, and is most prevalent in people ages 65 and older [2]. These symptoms associated with the disease appear to be similar to aging, but are not part of the natural aging process [2]. There is currently no cure for Alzheimer’s, with current drugs only treating the symptoms (memory decline, confusion and disorientation), but significant developments have been made in the past few years towards understanding the disease. Among those in the research community advancing Alzheimer’s research is Dr. Angel Martí, an Associate Professor of Chemistry, Bioengineering, and Materials Science and NanoEngineering at Rice University. Dr. Martí’s lab is focused on the treatment and diagnosis of amyloid-related diseases such as Alzheimer’s and Parkinson’s disease, both of which are centered around the Beta Amyloid Hypothesis.
The exact cause of Alzheimer’s is unknown, but several hypotheses have been formed in the past decades that may explain how the disease develops, most notably the Beta Amyloid Hypothesis. Beta amyloid (Aβ) is a sticky, hydrophobic protein found naturally in the brain in the form of monomers, its smallest molecular form. The monomers are derived from a larger protein known as Amyloid Precursor Protein (APP), whose original function is unknown. In patients with Alzheimer’s, Aβ monomers begin to aggregate and form Aβ oligomers; these oligomers may then aggregate further to form Aβ plaques, the most pathogenic form of Aβ [3]. Although Aβ plaques have been the main focus of Alzheimer’s research, Dr. Martí believes that understanding the development of Aβ oligomers—the aggregated form of Aβ proteins—is equally critical. Unlike plaques, Aβ oligomers are soluble in the blood and tissue fluid, allowing them to diffuse to different parts of the brain. This is particularly damaging since the oligomeric form of Aβ kills neurons as it diffuses. As Dr. Marti describes, “if Aβ is toxic [and] kills neurons, then as neurons start to die in patients with Alzheimer’s, the symptoms associated with [Alzheimer’s disease] will start.”
Taking this into consideration, Dr. Martí and his lab have created a ruthenium-based fluorescent complex, based on a concept known as fluorescence anisotropy, which tracks the development of Aβ oligomers in the brain. Fluorescence anisotropy is centered around the polarization of light, where “molecules can only absorb light that is in the direction of their transition dipole moments”. In other words, molecules can only absorb polarized light if they are oriented in the right direction, and will then rotate and emit light, resulting in a different polarization. However, since the molecules are extremely small, their high rotation speed results in the emission of light in multiple directions, depolarizing the light; the molecules can only emit polarized light in a specific direction when rotated more slowly. “Using fluorescence anisotropy, what you can measure is something that is proportional to how fast the molecules can rotate in solution.” The speed of the molecules is measured using a probe, which can bind to molecules if they are large enough. Aβ monomers are very small and are unable to interact with the ruthenium complex, “but once Aβ monomers start coalescing into bigger oligomers, then the probe can bind to the oligomers. And then, that probe that was rotating very, very fast before now rotates at the same rate as the big oligomer.” Using this complex, Dr. Martí and his lab may eventually be able to track the development of Aβ monomers into oligomers in Alzheimer’s patients by monitoring the changes in the speed that the probe rotates.
What can this be used for? The ruthenium-based fluorescent complex is still being refined and developed, but Dr. Martí says that it will eventually be used to “visualize or track [Aβ aggregation] in real time,” which will allow his lab to “test different drugs or molecules that might interact with these oligomers, and either break them apart or inhibit their formation”. Beyond its various applications, Dr. Martí believes that fluorescent complex may be further improved or by modifying the metal complex for increased binding efficiency, and possibly even modifying it to bind to proteins of other diseases. While this complex is not a cure for Alzheimer’s, it is undoubtedly a significant development in tracking the impact of potential cures.
Works Cited
[1] Alzheimer’s Association. Alzheimer’s Disease Facts and Figures. https://www.alz.org/alzheimers-dementia/facts-figures (accessed Nov. 15, 2019).
[2] NIH National Institute on Aging. What is Alzheimer’s Disease? https://www.nia.nih.gov/health/what-alzheimers-disease (accessed Nov. 15, 2019).
[3] Alzheimer’s Association. Beta-amyloid and the Amyloid Hypothesis. https://www.alz.org/national/documents/topicsheet_betaamyloid.pdf (accessed Nov. 15, 2019).
[4] Rice University. Angel Martí Group at Rice University. https://martigroup.rice.edu/(accessed Nov. 15, 2019).