Dennis Selkoe on the Amyloid Hypothesis of Alzheimer's Disease
Special Topic of Alzheimer's Disease Interview, MARCH 2011
I'd also like to find out more about proteins that misfold in other brain diseases. One my lab is studying now is the protein alpha synuclein, which I think is going to turn out to be for Parkinson's disease what amyloid beta protein is for Alzheimer's. We're working on how that protein misfolds and aggregates and causes trouble for neurons, although it's going to be a somewhat different mechanism than how the amyloid beta protein causes trouble in Alzheimer's.
Of all the research in Alzheimer's done in the past five years, which experiments did you read about and think, "I wish I had done that?"
I have to give more than one example. I can't elevate one over several others. So, one would have been the discovery that a duplication of the APP gene in otherwise normal people that can precipitate a very nasty form of Alzheimer's. That discovery was made in France about six years ago.
I thought that was very clever because we knew that mutations in the APP gene could cause Alzheimer's and we knew that trisomy 21 could also cause an Alzheimer's phenotype, but these folks in France did some clever genetic sleuthing to find rare families that had an extra copy of just the APP gene and maybe two or three other genes right around it on chromosome 21. These people were physically and mentally normal throughout their lives, until they got Alzheimer's. That was a great smoking gun for the amyloid beta hypothesis. I would have loved to be associated with that.
Another discovery that I admire greatly was done by Lennart Mucke at UCSF. He got some mice that had the tau gene deleted genetically, and he crossed those "tau-minus" mice with mice that had the human APP gene inserted into their genomes. He showed that while amyloid beta protein still built up in the brains of these crossed mice, they had far less behavioral problems than the regular APP transgenic mice with tau. In other words, tau played a big role.
Tau is a subunit of the Alzheimer's neurofibrillary tangles. And Mucke and his colleagues were able to show that if mice don't have tau, they still get the amyloid pathology of Alzheimer's but they don't get all that much behavioral trouble. They have behavioral symptoms but much less. I thought that was really cool, and I would have enjoyed coming up with that myself.
"...my lab is studying now is the protein alpha synuclein, which I think is going to turn out to be for Parkinson's disease what amyloid beta protein is for Alzheimer's."
We did follow up on it in our laboratory with a paper that's almost in press (I hope) at PNAS. I'm very excited about it. We said, "Let's reduce Mucke's discovery to an even simpler form." We took some primary cultured neurons from rats and put them in a dish and then put on top of them some soluble amyloid beta dimers that we isolated from the brains of Alzheimer's patients after they died. The idea was to see if those amyloid beta dimers are themselves necessary and sufficient to induce alterations of tau. And we showed it quite nicely. When we put on these amyloid beta dimers, even in exquisitely small amounts, they were very potent.
First we induced an increased phosphorylation of the tau protein in these healthy neurons. Then we saw the microtubule cytoskeleton begin to collapse, and then the nerve endings degenerate into what we call neuritic dystrophy. So, in a test tube, a culture dish, we can show how AD brain amyloid beta protein dimers directly induce these tau alterations, the abnormal phosphorylation of the tau protein, just about the same as happens in the Alzheimer's brain.
Then, when we knocked down tau in the neurons using RNA interference, we rescued the neurons and they didn't go on to degenerate. That was really cool. And we also showed that if you treat the neurons with the very same antibody that's in phase III clinical trials, it prevents the bad effects of the amyloid beta protein dimers on tau and on the neuritic architecture.
We also learned in this work that the neurons have to become more mature, somewhat older, to see these effects. If you take neurons that are just seven days in the culture dish, they don't have any of the bad effects from the amyloid beta dimers. Only after 14 or 18 days in culture or, best of all, 21+ days, will the neurons have the right protein expression program underway to really suffer from the amyloid beta dimers. Before that, they're resistant. Biologically, that's very interesting. I like to think that this experiment shows the bridge between the two classical lesions that Alzheimer's first described in 1906—plaques and tangles.
If we lived an ideal scientific environment and you had unlimited resources to do a single experiment, something you couldn't afford now, what would you do?
I would design a clinical trial of 18 months' duration, in which we would take only people in the very mild stage of Alzheimer's, people but who do have the disease, who do have symptoms of memory trouble, but are in the early stage. This wouldn't be a prevention trial. We would use extensive scanning of brains with Pittsburgh compound B or a similar dye to find these subjects—that's expensive, perhaps about $3,000+ per patient, and we'd want at least 500 patients. Then, we would have to test their spinal fluid for amyloid beta protein 42 levels, which should be decreased.
But the main point is to give the treatment in the early stages of this disease and to enrich the trial population with subjects that we know all have amyloid deposition in their brains. We don't want to treat people with another kind of dementia, because amyloid drugs won't help those people. So we get 500 or perhaps even 800 to 1,000 patients, we give a third of them placebo and the other two-thirds one or another dose of the treatment. If you ask which treatment, I'd say probably an antibody to the amyloid beta protein, because we know the most right now about how antibodies work. That would be the experiment. It would be complicated and very expensive, but it's the experiment I'd most like to do.
How expensive is very expensive?
If we're doing a phase III trial, it would probably cost in the neighborhood of $100 to $200 million or more to do it right. We'd have to scan the people, follow them carefully, pay for all the costs incurred to undergo the experimental treatment, the doctors' and nurses' visits, etc. We'd have to do the spinal fluid exams. Probably north of $200 million. That's not a laboratory experiment, but if you ask me what I would most like to do as a scientist, as someone who's worked on this for so long, that would be it. I'd like to design a clinical trial that would be even better than the ones underway right now. I'd like to see this disease defeated.
Dennis J. Selkoe, M.D.
Harvard Medical School
and
Brigham and Women's Hospital
Boston, MA, USA
DENNIS SELKOE'S MOST CURRENT MOST-CITED PAPER IN ESSENTIAL SCIENCE INDICATORS:
Hardy J, Selkoe DJ, "Medicine—the amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics," Science 297(5580): 353-6, 19 July 2002 with 2,483 cites. Source: Essential Science Indicators from Clarivate .
ADDITIONAL INFORMATION:
- Read a previous features (and podcast) with Dennis Selkoe within ScienceWatch.com.
KEYWORDS: ALZHEIMER’S DISEASE, AMYLOID BETA, IMBALANCE, BRAIN, CASCADE, GENES, FAMILIAL FORMS, SPORADIC FORMS, CEREBRAL SPINAL FLUID, DOWN SYNDROME, CHROMOSOME 21, PATHOLOGY, PRESINILINS, GAMMA SECRETASE, BETA SECRETASE, AMYLOID PRECUSOR PROTEIN, CLINICAL TRIALS, GAMMA SECRETASE INHIBITOR, NOTCH TOXICITY, NERVE CELLS, ANTIBODIES, PROTEIN MISFOLDING, TRISOMY 21, TAU, PHOSPHORYLATION, DIMERS, MEMORY, EARLY STAGE, BRAIN SCAN, COST.