SENS Research Foundation and Buck Institute to Collaborate on a New Approach to Clearing Neurofibrillary Tangles
The SENS Research Foundation staff have over the past decade pioneered the field of medical bioremediation, mining the bacterial world for enzymes capable of breaking down the various forms of metabolic waste associated with aging and age-related disease. Suitable enzymes can form the basis for rejuvenation therapies that work via clearance of these waste products, and thus far the SENS teams have spun off the results of their work into development programs at Human Rejuvenation Technologies, to treat atherosclerosis, and Ichor Therapeutics, to treat macular degeneration. Today the SENS Research Foundation announced a new collaboration with the Buck Institute for Research on Aging in order to apply this same approach to the clearance of altered forms of tau protein that cause harm in Alzheimer's disease and other tauopathies. Much of present day Alzheimer's research focuses on clearance of amyloid, but it is becoming clear that both amyloid and tau aggregates are involved in the pathology of the condition. Unfortunately, while there are some signs of progress, work on tau clearance lags years behind the efforts put into amyloid clearance. Here is a chance for that side of the field to catch up:
The SENS Research Foundation (SRF) has launched a new research program in collaboration with the Buck Institute for Research on Aging. A leading expert on age-related neurodegenerative diseases will be leading the project in the Andersen lab at the Buck. The program is focused on the formation of tau tangles in the progression of neurodegenerative diseases. It will explore the elimination of these age-related waste products in brain cells, using the same approach that SRF has applied in its atherosclerosis and macular degeneration research projects in recent years. The Andersen lab will bring its own world-leading expertise in age-related neurodegeneration to the project. "Our ultimate goal is to find treatments for Alzheimer's and Parkinson's disease. Working with SRF will enable us to look at whether it is possible to use a new method to reverse and prevent the formation of tau tangles, which will help us make significant progress in addressing these complex disorders."
This research has been made possible through the generous support of the Forever Healthy Foundation and its founder Michael Greve, as well as the support of our other donors. The Forever Healthy Foundation is a private nonprofit initiative whose mission is to enable people to vastly extend their healthy lifespans and be part of the first generation to cure aging. In order to accelerate the development of therapies to get aging under full medical control, the Forever Healthy Foundation directly supports cutting edge research aimed at the molecular and cellular repair of damage caused by the aging process. "We are extremely proud to be supporting this project and partnering with the Buck. With this and other collaborations we are planning, SRF looks forward to expanding our contribution to the advancement of medical research on pathologies associated with human aging."
Is this the first time these bio remedial bacterial enzymes have been directed against an intra-cellular but not intra-lysosomal target? Would this make delivery of the enzymes produced by a gene therapy easier or harder?
Also is there a rough number of the types of intra-cellular junk that will need to be dealt with in this manner?
Reason, what is your opinion on Proclarabio (formerly Neurophage) and their product NPT088? To me this seems the most promising as it targets multiple protein fragments including both amyloid and tau and they are moving toward human trials.
@Link: Seems interesting, but the proof is in the doing, as ever. Hopefully their method continues to show promise as it advances through the regulatory system.
@Jim: I can't comment on the first question, but I believe that there are a lot of types of junk, and no complete map at this time to link various types to specific damage, or degree of contribution to overall damage. The fastest way to get that map is to start removing the junk, one by one. So I don't imagine that this question will have a good and comprehensive answer before the research community is well into the first half dozen types of waste compound.
Hi Jim,
First, to be clear, the project is in its early stages, and we and Dr. Andersen haven't yet defined our exact approach. As your question rightly presupposes, neurofibrillary tangles - a key form of intracellular aggregate involved in neurodegenerative aging, including Alzheimer's - are cytosolic inclusions. So one approach would be to go after the NFT directly in the cytosol.
No, we haven't done this to date, nor to my knowledge has anyone else in a therapeutic context: the other intracellular targets we've gone after to date (oxidized cholesterol products and A2E) are lysosomal aggregates, as you and most FA! readers will know. It would actually be a lot easier in one sense to use this approach, because it wouldn't require the extra modifications of the enzyme structure and the addition of a targeting signal to get it into the lysosome: it would automatically be produced in or released into the cytosol. However, it would potentially make enzyme selection harder, as there would be a risk of off-target effects of the enzyme on proteins other than NFT in the cytosol: there are all kinds of proteases that would degrade NFT, but the challenge would be to find one that did so selectively, rather than chopping up other, healthy proteins and organelles. By contrast, we wouldn't worry about off-target effects in the lysosome: anything else that gets hit in the lysosome is there to be degraded anyway.
However, we're also exploring the possibility of a kind of "bank shot" against NFT. Tau itself is a substrate for chaperone-mediated autophagy (CMA), so it's possible that the reason why NFT form and accumulate in the neuron is because lysosomal function is impaired in aging neurons by something else (such as lipofuscin or beta-amyloid (though I think the evidence is pretty strong against the latter in particular). So one approach we may take is to first design some experiments to test this possibility, and then depending on the cause of impairment see whether eliminating it and restoring the lysosome's ability to degrade tau would lead the cell to take apart the NFT on its own and send them for normal lysosomal processing.
It's a little astonishing that no one has ever tried targeting intra-cellular Tau tangles before. Or maybe they have, and I am just ignorant of this.
Thanks for the reply Michael. It is interesting that NFT may be due to loss of lysosomal function. That does explain why, excluding mutations in the Tau gene, individuals don't seem to get unlucky and get early NFTs and Taupathies at a young age, unlike something like cancer.
The timing of this announcement, and Dr de Grey's recent highlighting of a means to develop specific proteases, makes me suspect this development may have prompted the funding.
https://www.ncbi.nlm.nih.gov/pubmed/26730612
Jim: Well, AFAIK, research on tau removal, like other amyloids, has been centered on antibodies, so they can't target intracellular tau.