Study provides a new understanding of Alzheimer’s disease
Alzheimer's is a devastating disease with no cure and very limited treatment options. But researchers think they may be making some progress. They've discovered a molecular switch in the brain that triggers memory loss and in a study on mice they have been able to reverse the process.
Transcript
00:00 Alzheimer's has traditionally been defined by the presence of a substance or a plaques
00:07 in the brain which are made of a substance called amyloid.
00:09 They're actually, when you look at a brain under a microscope or in later stages you
00:13 can see it quite clearly, they literally look like tooth plaque in the brain.
00:18 And scientists for maybe 40 years have thought that this plaque is the cause of the disease
00:23 and consequently they've been working very hard to try and work out how to get rid of
00:27 that plaque.
00:28 Unfortunately with no major success, there's a recent drug that's just been approved in
00:33 the US, there's a very, very small effect in a very small percentage of people.
00:38 And so you've taken a completely different approach to this, how have you approached
00:42 it?
00:43 Right, so we've actually been saying for some time that we need to rethink this disease
00:47 and that amyloid alone is not the answer.
00:49 We're not saying it isn't involved in the disease, of course you can't say that, but
00:52 we are saying that it's not going to be the solution.
00:54 What we've been saying instead is that it's been known for a very long time that in Alzheimer's
01:00 disease there's a loss of what are called the nerve cell connections in the brain, they're
01:04 given a name called synapses, they're little physical connections between nerve cells.
01:08 There's a hundred trillion of these nerve cells, at least a hundred trillion nerve cell
01:13 connections in the brain and what's been known for a long time that in Alzheimer's these
01:17 nerve cell connections are lost.
01:19 And the other piece of information that's known or believed through a hundred years
01:22 of neuroscience research is that these connections store memory.
01:27 So for us we're saying look it makes sense, if the nerve cell connections are being lost
01:30 in Alzheimer's and Alzheimer's is a disease where you're losing memory, clearly these
01:34 nerve cell connections must be part of what's going on in Alzheimer's and people don't dispute
01:38 that, they just haven't studied why it's occurring and whether it can be reversed.
01:42 And so have you worked out a way to restore those nerve cell connections?
01:47 This is the announcement that came as we published it in a peer review journal today, internationally
01:52 leading journal, and essentially what we were able to show is that we were able to restore
02:00 those nerve cell connections using a very sophisticated methodology which we can explore
02:05 in a minute.
02:06 But the most important discovery, the one that's the real eureka moment, was that by
02:11 restoring these nerve cell connections in the brain of an Alzheimer's model animal,
02:16 so we know that they're lost in the human so we replicated that in the animal model
02:19 of Alzheimer's, then you rescue those synapses and the model, and the animal then, you've
02:24 got restored memory function, 100% restoration memory function.
02:27 And rescued memory as well.
02:30 Right, well you can't bring back the memory that's been lost in this but you can actually
02:33 rescue the capacity for memory, which is just a tremendous, as you will understand, holy
02:39 grail of research for Alzheimer's.
02:41 And so take us through the mechanics of how you've been able to work this out then, that
02:45 the process of restoring those nerve cell connections.
02:49 Right, so we've been interested in the idea that synapses lead to memory loss in Alzheimer's
02:56 since the late 1990s.
03:00 So that sounds like a long time but in the history of science, this is a short time span
03:04 but for us it's a very big journey.
03:07 And we became aware, there was something we're calling a molecule, we're calling a switch,
03:13 a process, we're calling a switch in nerve cells, which we actually had kind of studied
03:18 in the 1990s when I was in the United States.
03:21 But we didn't really know what it did.
03:23 I saw that through human studies, this switch, we're calling it a switch, has turned, and
03:27 I'll explain why we call it a switch in a minute, it's turned down in the brain of Alzheimer's
03:31 patients.
03:32 We know that, you can see the data, you can see that from people who've passed away with
03:36 Alzheimer's, this switch has turned down.
03:38 We thought there's a good reason to think this might be involved in synapses, so we
03:42 forced in the animal, we said let's try and turn it on, increase its expression and see
03:48 if we can restore the synapses.
03:49 And indeed that's what happened.
03:51 We restored the synaptic connections so you've got many more synapses back in the animal
03:55 model now and you've restored the memory function which was just, as I said, a big eureka moment
04:00 for us and says the synapses are really important in Alzheimer's.
04:04 And so you mentioned the hundred trillion nerve cell connections in the brain.
04:08 Are there switches in each of those nerve cells?
04:13 And so can you go into any more detail about how physically or how you are stimulating
04:19 that?
04:20 I can.
04:21 So how we stimulate, so again just to try and keep it simple, I guess the way we think
04:29 about this, we're calling it a switch because it is like a switch on the wall and behind
04:33 that switch is a black box and that black box for mysterious reasons leads to changes
04:38 in the light going up or going down.
04:40 So in the same way that you can manipulate a switch in various ways, we used a very sophisticated
04:47 molecular genetic technique, I won't go into it here, but modern biology is mind-bogglingly
04:52 powerful in the animals that forces the switch on so you can't actually wind it down.
04:59 And so in the normal animal and in the human we know that the switch is turned down and
05:03 we know that in the animal and the human there's loss of synapses and what we did using this
05:07 sophisticated technique, we forced the switch on and then the synapses came.
05:11 We could actually see using our, again, molecular studies of the mice that we actually restored
05:16 the synaptic connections and that led to restoration of memory.
05:19 And you mentioned before that this doesn't lead to rescued memory, but are you excited
05:25 about the prospect of using this as prevention before memory is lost?
05:32 So yes, we are.
05:35 Let me just sort of put it into perspective in terms of the scientific journey and why
05:39 we think this is so important.
05:41 I like to give the example that everyone understands of antibiotics, right?
05:46 It took 200 years, believe it or not, maybe a bit longer for science to work out that
05:50 infection was caused by bacteria.
05:53 It wasn't known and the history of that is really controversial and you see science going
05:58 up and down as people didn't even Lee Van Hook who saw it under a microscope said, "One
06:02 of the greatest scientists I showed in our time, under the microscope, these microbes,"
06:08 and he didn't believe what he was seeing because it didn't accord with his current theories.
06:13 And then once we understood there were bacteria, then of course we could develop antibiotics,
06:18 discovered antibiotics.
06:19 Once we discovered antibiotics, we are where we are today very, very quickly.
06:22 A plethora of antibiotics, you go in now, you have an infection, we know what an infection
06:25 is, the average person knows what an infection is, you can treat it.
06:28 The same thing about this discovery.
06:30 What it says is, "Look, we've known that synapse loss occurs in Alzheimer's.
06:33 People have said it's probably important in memory.
06:35 We don't really know how it happens or why it happens or if restoring it will have a
06:39 benefit for memory."
06:41 The important concept of this paper is to say to the world, because we published it
06:44 in an international journal, all our colleagues around the world look at this, and what you're
06:49 saying to the colleagues around the world is, "This is where we need to look.
06:52 This is the way we need to go about treating it.
06:54 Let's work.
06:55 I'm hoping that you'll all get excited.
06:56 I'll go to meetings, I'll go overseas, I'll meet people, I'll say, 'Come on, we've got
06:59 to work on this, guys and girls and ladies,' and see if we can actually develop a drug
07:04 or a therapeutic strategy that can actually force these synapses back into humans."
07:08 - So you think this could well lead to a fundamental rethink of the way researchers are approaching
07:14 Alzheimer's?
07:15 - I strongly advocate that.
07:19 As Leeuwenhoek had in his situation where he was looking down the microscope and he
07:22 showed to a very famous person, "These are bugs.
07:26 These are things that are causing disease."
07:28 That person, he actually wrote, "Anything that didn't accord with his current theories,
07:34 his organs of vision were unable to see."
07:36 I think sometimes when you're putting something new forward, you're going to have to spend
07:39 some time explaining it to your colleagues, but this was done with an international team.
07:43 We led it here in Australia.
07:44 I'm proud of that.
07:45 Australian science is absolutely brilliant.
07:47 My colleagues here are fantastic.
07:50 The goal now is to convince our colleagues to take this forward to our colleagues to
07:53 see if they'll engage in the mission of trying to use this approach to bring about a cure
07:58 for a disease that is absolutely devastating.
08:01 - And as someone who's worked in this field for decades, what's it like to have a moment
08:06 like this?
08:07 - You know, I'll be very personal if I may.
08:09 My father recently passed away with dementia and Alzheimer's.
08:13 It's a very painful disease.
08:15 It's very slow.
08:17 It's funny when it starts, you know, you don't even recognize it.
08:21 Even myself as a trained in the field, it starts with...
08:26 And people with Alzheimer's early on are very good at masking it.
08:29 They have tricks that kind of mask it, so you don't actually...
08:32 That's one of the wonderful things about the brain.
08:34 But slowly but surely, it's a very long, arduous disease.
08:36 The care required for someone going through that.
08:39 My mother being, you know, so loving to my dad, but totally had to do this full time
08:46 all the time.
08:47 This is what's happening to millions of people around the world in Australia.
08:50 And so I think the feeling that we go to...
08:53 I go to work every single day.
08:54 I don't call it work.
08:55 It's a vacation.
08:56 It's a love.
08:57 I go every single morning.
08:58 I'm committed to doing something for this disease.
09:00 My team, been together 20 years.
09:02 We really want to make a change.
09:03 And when you get this discovery and you see the animals recovered in the way that we did,
09:08 it was like, wow, this is really, really important.
09:12 And then you've got to do another five years of work to actually show that it's real.
09:15 Your colleagues don't believe you when you first show the data.
09:17 So you've got to convince them through the peer review process.
09:20 And then when you get it published and you have a moment like this where we can talk
09:23 to you about it and explain to the viewers today what we've done.
09:27 It's a very, very fulfilling moment, but it's also, you don't really have time to rest.
09:31 You actually want to get back in there and take it forward.
09:34 Take it forward and make a difference going for the next few years and just really make
09:38 this into a treatment that can actually help people.
09:40 We're committed to that.
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