Mechanism: GPLD1 cleaves GPI anchors; TNAP as the key BBB target

1:27:22themselves, the TSA >> is what this thing is maintaining. >> Okay. I Yes. Okay. Very interesting. >> So, here's the mechanism. GLDD1 is something called a phospholipase. That's what the P the the uh D is there somehow. >> And what it's doing is its function is to cleave something called the GPI anchor. >> These are anchors that tether proteins to cell membranes. The cell has an outside. >> That's the cell membrane. And there's a bunch of proteins that are tethered to the cell membrane. You can imagine a boat on a dock, right? The boat is not actually attached to the to the dock. There's like rope that attaches a boat

1:28:02to the dock and a bunch of like those >> like sailor knots, right? >> Yes. >> That's a tethering protein. >> Okay. >> And what this GLD1 is doing is attacking that tethering protein. Okay. >> Now, why is that a good thing? >> Yeah. Like why? >> You would think that like if a protein is tethered to the to the cell membrane, you want to keep it there. >> Yes. >> Right. >> It's exactly what I think. >> That's that's what you should think. If there's too many proteins though on that cell membrane, what's going to happen to your dock? >> Uh the dock's going to break down. >> The dock's going to break down. If there's too many boats, that's why there's like you got to like pay for slips. You can't just like free-for-all dock to your to the dock, right? Yeah,

1:28:43>> if there's too many boats, the dock is going to float away and then and then it's just chaos. >> So, you've got to have a way to have slips and like untether boats that are causing the dock architecture to rupture. That is what GLD1 is doing. Okay, they they >> they got a target. >> This target must be on the bloodb brain interface. And then they used actually transcrytoics to figure out that there's this specific protein called TNAP tissue non-specific alkaline phosphotase. This is a boat that docks to the membrane. Yeah. >> Okay. >> And if and this thing on its own has its own like job, right? >> Okay. This particular T-nap protein, it

1:29:24involves promoting bone mineralization. And in the brain, it does a variety of other stuff. Okay. But in the brain, if it's anchored to the to the cell membrane, if there's too many of that anchoring, then the cell membrane of your blood brain barrier is going to start breaking down and then all of a sudden your tight junctions start becoming loose. >> That was the hypothesis. Okay. Okay. Okay. >> And the key action was that if you circulate this GPLD1 drug, which is something that cuts, it's a scissor for the ropes that tether the boat. >> Then what that's going to do is act as a molecular scissor. It's going to cut that anchor. The TNAP is going to go off

1:30:05>> and you're going to maintain the blood brain barrier structure >> and that is what is key. So to recap, >> yes, >> you exercise. >> Yes. >> The liver produces this GLD1 enzyme. Yes, >> that GLLDD1 enzyme that goes into the brain. >> Yes. >> And it maintains the bloodb brain barrier by cutting >> the anchor between this T-nap gene and the >> cells that maintain that bloodb brain barrier >> because the the T-nap the T-nap at too much volume begins to degrade the actual structure of these tight joints. Yes. in the bloodb brain barrier and they're not

1:30:46currently for whatever reason self-regulated. There are no slips. >> Yes. Yeah. I mean, yeah, that the the self-regulation is the GLLD1, >> right? Right. Right. Which >> that's what the front the function, >> right? >> GLD1 is kind of like the boat uh I guess the dock like >> Coast Guard. >> Yeah. The Coast Guard. It's like you don't have a >> Right. But the currently, at least in the context of this study, >> Yeah. The only source uh for the GL GPL D1 >> is exercise >> is the liver during exercise. >> That is in the context of what we're looking at. That is the only way we can generate enough coast guard people to patrol the docks to maintain the

1:31:27structural integrity of the blood being barrier which can then be a driving force for the uh the um >> uh the plaques we talked about earlier. >> Yeah. Because now when when when you know random stuff gets in that maybe starts denaturing the plaque proteins which causes amoid plaques which causes >> yes >> Alzheimer's okay this is >> it's like from the top down and I I think it's worth it's worth really like lingering on this for a bit right we've created a molecular cascading mechanism >> from exercise to preventing Alzheimer's >> right there's now a link between the two >> yes >> and it it's literally exercise the liver produces a specific

1:32:10exine which is this GLD1 that then goes to maintain the bloodb brain barrier once the bloodb brain barrier is maintained >> Alzheimer's gets reduced because maybe that is the key issue >> right it's the the key issues potentially there's no TSA preventing whoever wants to come into the airport getting into the airport >> exactly >> um and then what we're looking at when we had the amyoid hypothesis was a specific specific type of person that was getting through at the airport but not >> and like causing problems inside the terminal, >> right? >> But that was it's potentially just a single use case versus understanding the systemic structure. >> Exactly. Yeah. And let's just go through some of the experiments that they did.

1:32:51So they did alkaline phosphate labeling of TAP. Tap is this thing that the the boat that is docking too often. Yes. To the bloodb brain barrier. And you can see on the left there is old animals. There's lots of TAP >> along the blood vessels. And on the right is an old animal that does exercise, >> the amount of TENAP is drastically reduced. >> That's incredible. >> So there you can see just very much in the staining of this particular enzyme that we're getting a lot. They also did novel object recognition and Yaze, which are these behavioral tests for old mice, okay? Like if if the old mice have dementia, they can't do well on these where's the cheese type of task. But you could actually recover and reverse

1:33:34cognitive decline >> by treating old mice with GLD1. You could treat old mice with GLLD1 without having them do exercise. And then there was a profound reversal in the deficits in this particular behavioral maze, right? So they could find the cheese faster and all that other kind of stuff and remember where the cheese was. And just to be clear, what we're what you're saying here is um you can artificially