I am republishing this post from last October, because the excellent paper I’m going to write about has similar thinking.
Although the chemistry explaining why these mutations are associated with Alzheimer’s disease is exquisite and why they point to ‘the’ cause of Alzheimer’s disease — the amyloid fibril, billions have been spent in attempts to remove amyloid fibrils with no useful therapeutic result (and some harm)
Here’s the old post
The structure of the amyloid fibril formed by the aBeta42 peptide exactly shows why certain mutations are associated with hereditary Alzheimer’s disease. Here is a picture
https://www.alzforum.org/news/research-news/danger-s-bends-new-structure-av42-fibrils-comes-view
Scroll down to the picture above “Bonds that Tie”
If you need some refreshing on the general structure of amyloid, have a look at the first post in the series — https://luysii.wordpress.com/2021/10/11/amyloid-structure-at-last/
Recall that in amyloid fibrils the peptide backbone is flat as a flounder (well in a box 4.8 Angstroms high) with the amino acid side chains confined to this plane. The backbone winds around in this plane like a snake. The area in the leftmost loop is particularly crowded with bulky side chains of glutamic acid (single letter E) at position 22 and aspartic acid (single letter D) at position 23 crowding each other. If that wasn’t enough, at the physiologic pH of 7 both acids are ionized, hence negatively charged. Putting two negative charges next to each other costs energy and makes the sheet making up the fibril less stable.
The marvelous paper (the source for much of this) Cell vol. 184 pp. 4857 – 4873 ’21 notes that there are 3 types of amyloid — pathological, artificial, and functional, and that the pathological amyloids are the most stable. The most stable amyloids are the pathological ones. Why this should be so will be the subject of a future post, but accept it as fact for now
In 2007 there were 7 mutations associated with familial Alzheimer’s disease (10 years later there were 11). Here are 5 of them.
Glutamic Acid at 22 to Glycine (Arctic)
Glutamic Acid at 22 to Glutamine (Dutch)
Glutamic Acid at 22 to Lysine (Italian)
Aspartic Acid at 23 to Asparagine (Iowa)
Alanine at 21 to Glycine (Flemish)
All of them lower the energy of the amyloid fiber.
Here’s why
Glutamic Acid at 22 to Glycine (Arctic) — glycine is the smallest amino acid (side chain hydrogen) so this relieves crowding. It also removes a negatively charged amino acid next to the aspartic acid. Both lower the energy
Glutamic Acid at 22 to Glutamine (Dutch) — really no change in crowding, but it removes a negative charge next to the negatively charged Aspartic acid
Glutamic Acid at 22 to Lysine (Italian)– no change in crowding, but the lysine is positively charged at physiologic pH, so we have a positive charge next to the negatively charged Aspartic acid, lowering the energy
Aspartic Acid at 23 to Asparagine (Iowa) –really no change in crowding, but it removes a negative charge next to the negatively charged Glutamic acid next door
Alanine at 21 to Glycine (Flemish) — no change in charge, but a reduction in crowding as alanine has a methyl group and glycine a hydrogen.
As a chemist, I find this immensely satisfying. The structure explains why the mutations in the 42 amino acid aBeta peptide are where they are, and the chemistry explains why the mutations are what they are.
Abeta peptide, Amyloid structure, Arctic familial Alzheimer mutation, Dutch familial Alzheimer mutation, Familial Alzheimer’s disease, Flemish familial Alzheimer mutation, Iowa familial Alzheimer mutation, Italian familial Alzheimer mutation. No
Chemiotics II 