Absolutely. That’s a very interesting question, and it’s one of the most profound mysteries of all of Alzheimer’s disease. We know that amyloid builds up in the brain of some individuals that are destined to get Alzheimer’s disease, and that might take, what, 20 years or so. Then something happens, and the tau pathology begins, and once the tau pathology begins, it takes off and it spreads throughout the brain...
Absolutely. That’s a very interesting question, and it’s one of the most profound mysteries of all of Alzheimer’s disease. We know that amyloid builds up in the brain of some individuals that are destined to get Alzheimer’s disease, and that might take, what, 20 years or so. Then something happens, and the tau pathology begins, and once the tau pathology begins, it takes off and it spreads throughout the brain. But we don’t yet know the mechanistic connection between the A-beta pathology and the tau pathology. And what we’re doing in the lab is trying to figure that out. And what we’ve been showing in our recent publications and our recent work is that the amyloid plaque itself, which is made of the A-beta peptide, is toxic to the surrounding brain cells, the surrounding neurons. And there’s something about the contact of the axons of the neurons. Axons conduct the electrical activity between neurons and they’re very important for cognition and memory. There’s something about the amyloid plaque that causes those axons in the vicinity to swell up, and they become dysfunctional. They don’t do their job anymore. We think it has to do with the amyloid causing damage to the membrane of the axons, and that allows calcium to flow in. That disrupts the microtubules and the axonal transport that has to occur down the axon. That leads to the swelling, but it also causes a dysregulation of the kinases and the phosphatases that phosphorylate tau, and we believe that that’s what leads to the buildup of hyperphosphorylated tau. And then it goes on to create the tangles that spread throughout the brain. And we have evidence that these swollen axons around the amyloid plaque actually fill up with hyperphosphorylated tau. And we’re able, through different techniques, to make the dystrophic neurites decrease or increase. And if we decrease these swellings, which we call dystrophic neurites, then the tau pathology, the hyperphosphorylated tau, goes down. But if we use genetics to increase those swellings, then the hyperphosphorylated tau goes up. So we’re able to manipulate the tau phosphorylation up and down by changing the amount of these swellings, these axonal swellings that we call dystrophic neurites.
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