My first discovery was the major amyloid beta species that accumulates in the human brain is pyroglutamate A-beta that starts with pyroglutamate at position three. And we showed we can generate an antibody specific to this form of A-beta. And then this gave Eli Lilly, the technical and conceptual basis for generating donanemab. So it was 1995, more than 30 years ago, that we made this discovery...
My first discovery was the major amyloid beta species that accumulates in the human brain is pyroglutamate A-beta that starts with pyroglutamate at position three. And we showed we can generate an antibody specific to this form of A-beta. And then this gave Eli Lilly, the technical and conceptual basis for generating donanemab. So it was 1995, more than 30 years ago, that we made this discovery. And then it was, you know, transformed to therapeutic approach. I mean, over 30 years. So that was our first finding. And then we found that this specific form of A-beta-3 pyroglutamine may have something to do with A-beta metabolism. So we created internally radiolabeled A-beta-1-42 and we injected this into rat hippocampus to analyze the in vivo degradation. And A-beta was degraded very quickly with a half-life of about 18 minutes. And then using various protease inhibitors and also knockout mice, we found neprilysin as a major A-beta-degrading enzyme. And then we found that the target epitope, Abeta-3-pyroglutamate 42, is quite resistant to A-beta degradation with half-life of 90 minutes, whereas, as I said, the half-life of A-beta 1-42 was 18 minutes. So, A-beta 3B42 turns out to be very resistant to the in vivo degradation. And when we crossed our APP knockin mice with neprilysin knockout mice, this increased production of A-beta-3P42, which is an epitope of target of pyroglutamate. And this was caused by an increased expression of enzymes that contribute to A-beta-3B42 production. So we found the connection between neprilysin and donanemab via production of A-beta-3B42.
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