APP - amyloid clearance and production

Professor Dennis Selkoe compares the amyloid precursor (or parent) protein to a Bic pen. The clasp part seems to be the bad guy, and is part of a network involving presenilin and ApoE4.

In Alzheimer’s disease, we have struggled for the last two or three decades as to whether the problem is too much production or not enough removal of a-beta [amyloid beta]. There are two ways to fill a bathtub: you can turn up the spigot or you can block the drain more effectively. In Alzheimer’s [disease], it turns out, both are an issue. Some people clearly have too much a-beta production throughout life. Those are rare cases of familial Alzheimer’s in which there are mutations in two or three of the genes that manufacture a-beta. I’ll use a small prop that I always have with me – it’s a Bic pen and it turns out there is a protein in the brain, in millions of copies in everyone’s brain, called amyloid parent protein or APP. It has a front end and a back end, and it sits in the wall of a cell like this. So this is the inside – in here – and then there’s this big white part that sticks out. [Joking…] This Bic pen has been manufactured to be a two-scale model of amyloid parent protein or APP. The clasp on the pen is the bad guy in Alzheimer’s disease, as people like myself believe, and there are two cuts. There is a cut like this, and the pen or the amyloid parent protein comes apart, and this part is secreted from the cell and does good things. So it’s not an issue in Alzheimer’s [disease]. This part then remains in the cell wall, in the membrane of the cell. A second cut occurs right here at the ridge of the pen, and this part, the clasp, comes off. Just the clasp is called amyloid beta or a-beta. So just this piece, and if you make one it’s called a singlet or a monomer, and it’s okay, everyone makes it. If you make a lot more than a few, they find each other and pair up as a doublet, or a triplet, or a quadruplet, and you’re off to the races and that’s trouble. So there is an orderly cutting of this normal parent protein by two enzymes: one is called beta secretase, it cuts at the beginning of the clasp, and one is called gamma secretase and it cuts at the end. So the question: Is Alzheimer’s [disease] a problem of too much a-beta production or too little removal? And the answer is both. If you have too much activity here by so called beta secretase, and we know some Alzheimer’s [disease] patients have that, then you make too much a-beta and it builds up. If you have too much activity here, the so called gamma secretase – the second cut – you can also get Alzheimer’s [disease], and we know examples of that. The enzyme that does the second cut is called presenilin. It’s called presenilin because when it has a mutation is causes a very aggressive pre-senile form of Alzheimer’s [disease] that happens as early as the thirties, which is inconceivable. And yet other people with Alzheimer’s [disease] cut at a normal rate here and at a normal rate here, and they have a problem with removing the a-beta peptide from the brain. It’s a clearance problem, and there we know a gene that is responsible for clearance called ApoE4, and quite a lot of people have the ApoE4 trait in our society; they are much more prone to get Alzheimer’s [disease].