Apolipoprotein E and Alzheimer's Disease


November 10, 1994: I recently read somewhere that if everyone lived to be 140, they would end up with alzheimer's. This is part of the assumption I made with my model below (that beta-amyloid accumulation increases as you grow older since more of your neurons die). I could be wrong as to the reasons, still.

In the November 3, 1994 issue of Nature, there's an article called "Amyloid-associated proteins alpha1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments" (see References below). I am not sure how to place this result in the context of my model, namely that R112 in ApoE4 serves to act as a protease inhibitor, but ApoE4 protein does indeed increase filament formation. The relevant experiment to do would be to see if there is protease digestion of the beta-amyloid fragment and see if this happens in the prescence of ApoE4. Interestingly enough, the antichymotrypsin binds tightly to beta-amyloids and induces filament formation in people with Alzheimer's. This lends support to the fact that the beta-amyloid peptide is normally getting digested by a protease, but doesn't in the presence of alpha1-antichymotrypsin and ApoE4.


"An idea is only as good as the number of ways it lends itself to falsification."

I had to give a presentation about Apolipoprotein E (ApoE) and Alzheimer's disease. After looking at about half-a-dozen related papers and doing some structural analysis, it seems obvious to me how ApoE could participate in cerebral plaque formation (which is a cause/symptom of Alzheimer's). I first describe the line of reasoning that leads to model, the model itself, and then the preliminary structural studies I have done. Keep in mind that Alzheimer's rarely occurs before 60 and the when it does, it's referred to here as "early-onset", as opposed to "late-onset" which refers to Alzheimer's seen in people over 60. Apolipoprotein E is implicated in late Alzheimer's.


Model for ApoE involvement

ApoE4 binds the amyloid beta-protein and proceeds in targeting this protein for protease digestion. However, (i) the ApoE4 protein inhibits protease digestion and (ii) this could be made possible by several mechanisms, but given some of the facts (see below), we can make a hypothesis that ApoE4's arginine serves to act as a protease inhibitor the same way APPI's arginine inhibits protease.

As you age, more of your neurons die. The amyloid beta-protein is an integral membrane glycoprotein which will be a waste product of neuron degeneration. In order to metabolise this APP, excess ApoE will be produced in normal cells. But in the case of ApoE4, protease degradation will be inhibited! This explains the presence of ApoE4 and beta-amyloid accumulation as neurons degenerate.

Comparison of ApoE's arginine with BPTI/Trypsin Complex

The crystal structure of the receptor binding domain ApoE has been solved to 2.25 Angstrom resolution. The arginine at position 112 in ApoE4 is on helix 3. We attempted to dock the 4 helix bundle structure of ApoE onto the specificity pocket of trypsin in the same way BPTI (a trypsin inhibitor) inhibits trypsin. We chose trypsin since APPI is similar to BPTI in structure and it inhibits trypsin also. If this docking is accomplished so the arginine side chain is completely within the pocket, then there are clashes with the loops of the trypsin molecule. If we are away from the pocket by about 5 angstroms, then there are no clashes.

While this structural analysis is not completely convincing, it does not rule out the possibility that apoE inhibits protease digestion. It is conceivable the protease in question is not trypsin-like at all, and thus in this case the 4-helix bundle might dock in a better fashion. There are also other alternative models for the mechanism of protease inhibition as I point out.

Testing this model

It should be relatively easy to test this model---all one has to do is bind apoE to beta-amyloid and see if protease digestion is inhibited. While this is not conclusive, it will give sufficient evidence to carry on with this model (and try to figure out how protease is inhibited). The thing to do now is to find an experimentalist to do the experiment...


Pseudointellectual ramblings || Ram Samudrala || me@ram.org