Inflammation's role in Alzheimer's Disease

New insights into why people with Alzheimer's Disease lose their memory, and what causes the disease in the first place, have emerged thanks to a new study from Cambridge University, published in Communications Biology. In Alzheimer’s, a chemical called beta-amyloid builds up in the brain, and appears to “poison” nerve cells, although we didn’t know exactly how. But now immunologist Clare Bryant has discovered that this beta-amyloid can trigger an immune pathway in exposed brain cells. This, her experiments show, causes inflammation, deactivates the ability of nerve cells to store memories, and ultimately kills them, and she joined Chris Smith, to give him the details...

Clare - Yeah, Chris, it was very interesting. We had with Dave Klenerman in the Department of Chemistry a discipline-hopping grant from Alzheimer's Research UK, for Dave and I to look at our pathways in consistency. So what Dave does is measures how proteins clump; and amyloid beta or Abeta is a protein that's made naturally within the brain, but what it can do under disease conditions when it folds up incorrectly, it can form these kinds of clumps. So what Dave did was worked out how big the clumps were, and then I took clumps of different sizes, we put them on immune cells, and we looked to see whether or not they generate an inflammation-type response.

Chris - Just immune cells? Or brain cells more broadly?

Clare - Initially just the immune cells. And what we found when we did that was that actually the clumps of beta amyloid of a particular size would trigger a receptor that normally only responds to bacteria, called Toll-like receptor 4, and that then triggers inflammation.

Chris - Now are the particles then fooling the cells into thinking they're seeing sort of an infection almost? They're actually activating a pathway that you'd normally detonate when there's an infection? And that would normally be there quite naturally to ramp up inflammation and get rid of an invading organism, but in this case it's just something that's naturally and accidentally there.

Clare - Yeah, sort of. It's slightly different though. When a bacteria comes in contact with Toll-like receptor 4, it's like nuclear warfare, it's a massive response. But actually with the amyloid beta, what happens is you trigger the response, but it's a real slow burn. And that's really interesting because it comes on over a series of a few days, which means that you could potentially, if you were to inhibit or block this receptor, you might only need to block it every other day or every few days to actually prevent the beta amyloid-driven inflammation.

Chris - So if it's not ultimately killing the cells outright or detonating a nuclear war outright - it's just causing a low grade level of, almost tickling the cells - what consequences are there for them?

Clare - So the responses are really on the bystander cells, so to speak. The immune cells in the brain will trigger this inflammation and the production of this inflammation then kills neurons. And that's the key problem in the Alzheimer's response.

Chris - But does it have to kill them straight away? Because one of the other points you raised in the paper is that it also causes a memory deficit. And that comes earlier in Alzheimer's. People don't immediately present with a rotted-out brain, they present often with low grade symptoms of memory loss first.

Clare - Yeah. And this was the big surprise really. And so what actually happens is you can see in a brain slice - if you stimulate it you can measure something called long-term potentiation which is a measure of memory, and our collaborator Kai did this - but what was really surprising was we know that if you put amyloid beta into this preparation, you can see a drop in the development of long-term potentiation. If you put a TLR4 antagonist there, or a TLR4 blocker, you actually completely block this amyloid beta-driven suppression of the memory response, which is really interesting as well.

Chris - That's telling you two things then. One is that it doesn't have to just kill the cell initially, it can affect the ability of the cell to have this long-term potentiation, which is how we think memories are stored. So it could erode your memory circuits without actually killing the cell to start with. The second is - and this is tantalising - you're saying you can put a blocker drug on there and minimise the effects. So does this mean this is a new way potentially then to attack Alzheimer's?

Clare - Yeah, we think it might be. And that's very exciting. And as a consequence of all this work, we've been funded by Apollo Therapeutics to do exactly that, to develop new TLR4 blockers that can go into the brain and potentially interfere without the development of Alzheimer's disease at a number of different levels. And it speaks to the neuroinflammatory hypothesis - i.e., this is a hypothesis whereby inflammation in the brain is absolutely central to the development of Alzheimer's...

Chris - And that fits with other observations we've made already about Alzheimer's disease, which is that people say low levels of aspirin, for instance, seem to reduce the risk. Aspirins - anti-inflammatory. So that would fit with that. Certain dietary things like curcumin, which is in turmeric - antioxidant, which appears to be anti-inflammatory in the brain. It kind of fits then with what you're finding.

Clare - It does indeed, yes. It really underpins the importance of inflammation in the brain and the pathogenesis of diseases like Alzheimer's. And also it's true for Parkinson's as well, actually. And we see this as a really new, exciting therapeutic opportunity.