How to pronounce “amyl” in English

And so this was exciting.Amyloid does not show up in the right places in the brain.

relationship for sure. But, like I said earlier, it's really well understood.Amyloid, as I mentioned earlier, accumulates in the heart and it also accumulates in the brain during Alzheimer's.

We assembled this picture of how Alzheimer's disease starts.The amyloid hypothesis postulates that A beta is front and center.That accumulation of amyloid beta starts when we're healthy and probably reaches a near maximal level by the time patients--

So you introduce, in mice, those same genetic mutations that humans who have familial forms of Alzheimer's disease have and, lo and behold, these micedevelop amyloid plaques in their brain and they get demented.And so what if you administer a vaccine to these mice?

And so this was exciting.The amyloid protein, we really-- again, after decades of research-- really don't understand what it does normally, if anything.

those extra insulin parking passes prevent your brain from getting rid of a chemical called amyloid.And amyloid is actually the substance that accumulates in the brains of Alzheimer's patients.We also see that when people have insulin resistance, a structure in the brain called the hippocampus actually shrinks.

When it's time to grow, the seeds-- the barley corns or the grains-- make enzymes that convert that starch into sugar.The amylases that break it down.And why would you want to do that?

and wisdom that the elders have.So things like amyloid protein, for instance, which is associated with Alzheimer's risk, is being flushed out of the brain during sleep.

In plants, you put them under the microscope, and you can see the organelles that are essentially blasted open.They're called amyloplasts. I won't go into the detail, but essentially, you can zero in on particular organelles that are very sensitive, a little bit similar to the wayyour ears would be damaged by a loud explosion.

You either do that at the start.And so your salivary amylase breaks it down into sugars.

And the discovery of all these pathways ended up leading to the postulation of the amyloid hypothesis, which is this statement--that beta amyloid accumulation is the primary cause of Alzheimer's disease.This was revolutionary in the field.

That's trisomy 21. That's where you accidentally get three copies of chromosome 21 instead of the usual two copies.Guess where the amyloid precursor protein gene lives.It lives on chromosome 21.

The amyloid hypothesis postulates that A beta is front and center.That accumulation of amyloid beta starts when we're healthy and probably reaches a near maximal level by the time patients--like this 67-year-old woman that I told you about-- comes to my clinic.

It turns out that it's not so easy to create the kind of drugs that you put into a pill-- small molecules that you can take as a pill and somehowdo something to this amyloid protein to neutralize it.That turns out to be not so straightforward.

This paper was published in "Nature." Several biotechnology companies were already all over this.They had amyloid vaccines ready to give to humans.And so that was actually being done in parallel.

And so this was exciting.Not true of amyloid.

That's toxins in your brain that haven't been washed out during the night.And that beta amyloid is something that, it also reduces neurogenesis.How are we doing on time?

And we need to fix that.Then there's amyloidosis, which actually has been discovered quite recently to be a major killer of the really elderly.People who live more than 105, 110, it turns out that most of them, certainly half of them, die of a disease called senile cardiac amyloidosis, which

relationship for sure. But, like I said earlier, it's really well understood.It's not just amyloid accumulating.

There's an enzyme in our saliva that does.There's an amylase, an enzyme that digests starch, in our saliva that begins that process.Yeast can't do either of those things.

Koji is a fungus.It makes proteases and amylases.It breaks down proteins, breaks down starches.

So it kind of impacts on both areas.happens where some of the amyloid plaque that builds up in the brain that can tangle and get entangled with our neurons,

All right. So that makes sense.That's supportive evidence that amyloid is bad for you.Probably most compelling was genetic evidence of the importance of A beta.

The optimistic view of this graph is look how resilient the brain is.It can withstand a lot of amyloid plaques and a lot of tau tangles before a patient exhibits the first symptom.So symptoms are long-delayed in time from the accumulation of the damage in the brain.

Drug companies are starting to glom onto this and say, hey, we've got a goldmine here.We need to develop drugs against this amyloid protein.It turns out that it's not so easy to create the kind of drugs that you put into a pill-- small molecules that you can take as a pill and somehow

So this suggested to the field that the vaccine did what it was supposed to do.It presumably helped to clear amyloid plaques out of the brain, but it was a little bit frustrating that it didn't seem to have any effect on the clinical courseof the disease. So vaccines aren't safe because, as I said, you can't turn off the immune system once it starts.

And so this was exciting.They required people to have amyloid PET imaging in order to get into the trial.

And so this was exciting.It seems to be downstream of beta amyloid.

And so this was exciting.that have come from beta amyloid trials.

relationship for sure. But, like I said earlier, it's really well understood.down to this thing called amyloid.

There's a question over there which I will take in a moment.Extracellular junk-- this is stuff like the amyloid that form plaques in Alzheimer's disease.And this is important in the same kind of way that molecular garbage inside the cell is important.

He said, oh, it's all in his genes.and compare them using PET to look at amyloid and MRI to look at hippocampal volume and looking at cognitive function testing and biomarkers

not a very creative name.And we came to understand that some cleavage event-- so that amyloid precursor protein gets cut at two different places in orderto liberate this short string of amino acids that is the A beta peptide.

It turns out, that she had a point mutation-- just a single element of her DNA was changed in a protein thatmediates one of those cleavage events in the amyloid precursor protein to liberate A beta.Makes that enzyme work too much.

So just single genetic changes that lead to an overproduction of this one protein are sufficient to cause Alzheimer's disease.And so scientists really got excited about this amyloid hypothesis.And now we think we're on a pathway towards curing the disease because now we have the causative protein in the brain.

So bear that in mind.So again, amyloid hypothesis-- here we are now, in the 1990s and everybody in the scientific field is super excited about the amyloid hypothesis.And now, drug companies-- so now we're getting to the biotechnology part of the talk.

And so this was exciting.So they had to demonstrate positive evidence that they actually had amyloid in their brain-- in other words, that they truly had Alzheimer's disease.

And so this was exciting.so about one year-- produce reductions in how much amyloid is in the brain, measured by that amyloid PET imaging.

And so this was exciting.And given the number of failures of drugs that target beta amyloid, a number of us are wondering, is the amyloid hypothesis dead?

And the glial cells go and they just pick up, particularly the beta amyloid.Now, beta amyloid plaque is what accumulates in Alzheimer's.It's something we want to get rid of in the brain.

We've come a long way in biology in that time.Molecular garbage outside the cell-- there's something called senile cardiac amyloidosis which is now known to be the number one killer of people

Child support payments-- this guy, stay away from this guy.You can have gum all over your brain, amyloid proteins in your brain, and be clear-minded.

that the brain just doesn't know what to do with.And the discovery of all these pathways ended up leading to the postulation of the amyloid hypothesis, which is this statement--that beta amyloid accumulation is the primary cause of Alzheimer's disease.

And so this was exciting.But this great technology came into widespread use-- the use of an amyloid PET tracer.

And so this was exciting.So you put people into the scanner at baseline to make sure they have amyloid in the brain.

And one of the reasons for that is because when you have that parking problem and your body produces extra insulin parking passes,those extra insulin parking passes prevent your brain from getting rid of a chemical called amyloid.And amyloid is actually the substance that accumulates in the brains of Alzheimer's patients.

And it actually produces glucocorticoids that are neurotoxic, that actually begin to kill some of the cells in the hippocampus.And cognitive reserve, then when beta amyloid, if it does begin to accumulate, you are protected from it, for a very, very long time.

Because wakefulness is low-level brain damage.One of the sticky toxic proteins that it washes away at night is a protein called beta amyloid.And if you deprive rats of sleep, they immediately start to escalate the amount of this Alzheimer's protein in their brain after just one night.

So there's these characteristic changes of plaques and tangles.These plaques are made up of a protein that we came to discover called the beta-amyloid protein.So these plaques are in the gray matter.