AmyloSENS: Removing junk from between cells
Extracellular junk is accumulations of sticky, malformed proteins that no longer serve their function, but instead impair cell or tissue function by their presence. Extracellular junk is different from extracellular cross-linking, which is a form of damage that occurs between structural proteins and impairs their ability to move. Most extracellular junk is termed "amyloid" of one variety or another.
The most well-known form of extracellular junk is beta-amyloid: the stifling, web-like material that forms plaques in the brains of patients with Alzheimer's disease, and also (more slowly) in everyone else's, and impairs cognitive function. There are also a variety of similar aggregates that form in other tissues during aging and contribute to age-related diseases, including islet amyloid in Type II diabetes and senile cardiac amyloidosis, which is a major contributor to heart failure. In fact, there is some evidence that senile cardiac amyloidosis may be the main cause of death in people who survive beyond age 110.
Extracellular aggregates can be removed from the brain and other areas of the body by specialized antibodies that hone in specifically on them and remove them from the tissue. There two main ways to introduce these antibodies into a person: “active” and “passive” vaccines. “Active” vaccines introduce a small fragment of the amyloid to stimulate the cells of the immune system to target the amyloid and remove it. “Passive” vaccines involve making the antibodies outside of the body, and introducing them directly via injection.
More recently, a third and extremely promising variation on this approach has been developed. Dr. Sudhir Paul at the University of Texas-Houston Medical School discovered that a subset of human antibodies have catalytic activity against a particular antigen, breaking it down into smaller and less harmful fragments instead of trapping it for removal or destruction by other immune cells.
Using these new, catalytic antibodies as therapies for targeting amyloids offers some potential advantages over the “sequestering” antibodies used in other amyloid-targeting vaccines. One is that it is expected to reduce the dose needed to effectively clear extracellular aggregates from tissues. This is because sequestering antibodies must trap and then transport just one amyloid molecule at a time, whereas catalytic antibodies bind to an amyloid molecule, chop it up, and then move onto the next, one after another, allowing each antibody molecule to quickly destroy multiple amyloid molecules. Another is that catalytic antibodies come from a class that seems to be transported more efficiently across the barrier that protects the brain from being penetrated by foreign substances in the general circulation, whereas the sequestering antibodies are of a class that has a much harder time making the passage. This is, of course, important when targeting the beta-amyloid protein in the brain. And last but not least: sequestering antibodies probably need to be drawn back across this same barrier, with their captured beta-amyloid in tow, in order to get rid of their cargo. This passage of a large antibody-amyloid complex is also likely difficult, and may pose a risk of inflaming the brain if it is so inefficient that it causes a traffic jam of sorts at the juncture between brain and blood. Because catalytic antibodies destroy their target, they do not need tocross back across the barrier to dispose of it, but can safely release the cleaved beta-amyloid fragments and go on cleaving more beta-amyloid right where they are in the brain.
Amyloid-targeting vaccines are currently a hot area of scientific research in the Alzheimer’s disease field: in fact, several vaccines targeting beta-amyloid are currently in advanced clinical trials, and others are in various stages of animal research. The most ambitious of these trials is the Alzheimer’s Prevention Initiative: a five-year, $100 million study testing to see if one beta-amyloid vaccine can prevent the disease in people whose genes cause them to produce more beta-amyloid than most people do, and who therefore develop Alzheimer’s disease at much younger ages than the rest of us.
Research Funded by SENS Research Foundation
AmyloSENS at the University of Texas-Houston Medical School and Brigham and Women's Hospital at Harvard University
As noted above, the accumulation of extracellular aggregates in the heart over time cause senile cardiac amyloidosis (SSA) as well as isolated atrial amyloidosis (IAA). Removing these aggregates is necessary to rejuvenate the structure and function of the aging heart. SENS Research Foundation is funding work by Drs. Sudhir Paul at the University of Texas-Houston Medical School and Brian O’Nuallain at Brigham and Women's Hospital at Harvard University, to develop antibodies that would target the identification and catalytic breakdown of the aggregates responsible for these diseases, letting aging hearts beat with the freedom of youth.
For a more in-depth account of extracellular aggregates and how to remove them, see the chapter “Cutting Free of the Cellular Spider Webs” in Ending Aging.
Click here to view a list of SRF-funded academic publications relevant to AmyloSENS, or click here for a much more comprehensive reading list of third-party publications on this topic.