“Thinking about pathologic changes in neurologic disease has been simplistic in the extreme. Intially both senile plaques and neurofibrillary tangles were assumed to be causative for Alzheimer’s. However there are 3 possible explanations for any microscopic change seen in any disease. The first is that they are causative (the initial assumption). The second is that they are a pile of spent bullets, which the neuron uses to defend itself against the real killer. The third is they are tombstones, the final emanations of a dying cell.” I’ve thought this way for years, and the quote is from 2012: https://luysii.wordpress.com/2012/07/26/research-on-alzheimers-disease-the-bad-news-the-good-news/.
We now have some evidence that the senile plaque may be just a tombstone marking a dead neuron. Certainly attempts to remove the plaques haven’t helped patients despite billions spent in the attempt.
A recent paper [ Proc. Natl. Acad. Sci. vol. 117 pp. 28625–28631 ’20 –https://www.pnas.org/content/pnas/117/46/28625.full.pdf ] not only provides a new way to look at Alzheimer’s disease, but immediately suggests (to me at least) a way to test the idea. If the test proves correct, it will turn the focus of Alzheimer disease research on its ear.
Not to leave anyone behind, the senile plaque is largely made of a small fragment (the aBeta peptide 40 or 42 amino acids) from a much larger protein (the amyloid precursor protein [ APP ] — with well over 800 amino acids). Mutations in APP with the net effect of producing more aBeta are associated with familial Alzheimer’s disease, as are mutations in the enzymes chopping up APP to form Abeta (presenilin1, etc.).
The paper summarizes some evidence that the real culprit is neuronal uptake of the Abeta peptide either as a monomer, or a collection of monomers (an oligomer) or even the large aggregate of monomers seen under the microscope as the senile plaque.
The paper gives clear evidence that a 30 amino acid fragment of Abeta by itself without oligomerization can be taken up by neurons. Not only that but they found the protein on neuronal cell surface that Abeta binds to as well.
Ready to be shocked?
The protein taking Abeta into the neuron is the prion protein (PrPC) which can cause mad cow disease, wasting disease of elk and all sorts of horrible neurologic diseases among them Jakob Creutzfeldt disease.
Now to explain a bit of the jargon which follows. The amino acids making up our proteins come in two forms which are mirror images of each other. All our amino acids are of the L form, but the authors were able to synthesize the 42 amino acid Abeta peptide (Abeta42 below) using all L or all D amino acids.
It’s time to let the authors speak for themselves.
“In previous experiments we compared toxicity of L- and D-Aβ42. We found that, under conditions where L-Aβ42 reduced cell viability over 50%, D-Aβ42 was either nontoxic (PC12) or under 20% toxic . We later showed that L-Aβ is taken up approximately fivefold more efficiently than D-Aβ (28), suggesting that neuronal Aβ uptake and toxicity are linked.”
Well, if so, then the plaque is the tombstone of a neuron which took up too much Abeta.
Well how could you prove this? Any thoughts?
Cell models are nice, but animal models are probably better (although they’ve never resulted in useful therapy for stroke despite decades of trying).
Enter the 5xFAD mouse — it was engineered to have 3 mutations in APP known to cause Familial Alzheimer’s Disease + 2 more in Presenilin1 (which also cause FAD). The poor mouse starts getting Abeta deposition in its brain under two months of age (mice live about two years).
Now people aren’t really sure just what the prion protein (PrPC) actually does, and mice have been made without it (knockout mice). They are viable and fertile, and initially appear normal, but abnormalities appear as the mouse ages if you look hard enough. But still . . .
So what?
Now either knock out the PrPC gene in the 5xFAD mouse or mate the two different mouse strains.
The genes (APP, presenilin1 and PrPC) are on different chromosomes (#21, #14 and #20 respectively). So the first generation (F1) will have a normal counterpart of each of the 3 genes, along with a pathologic gene (e.g. they will be heterozygous for the 3 genes).
When members of F1 are bred with each other we’d expect some of them to have all mutant genes. If it were only 2 genes on two chromosomes, we’d expect 25% of he offspring (F2 generation) to have all abnormal genes. I’ll leave it for the mathematically inclined to figure out what the actual percentage of homozygous abnormal for all 3 would be).
What’s the point? Well, it’s easy to measure just what genes a mouse is carrying, so it’s time to look at mice with a full complement of 5xFAD genes and no PrPC.
If these mice don’t have any plaques in their brains, it’s game, set and match. Alzheimer research will shift from ways to remove the senile plaque, to ways to prevent it by inhibiting cellular uptake of the abeta peptide.
What could go wrong? Well, their could be other mechanisms and other proteins involved in getting Abeta into cells, but these could be attacked as well.
If the experiment shows what it might, this would be the best Thanksgiving present I could imagine.
So go to it. I’m an 80+ year old retired neurologist with no academic affiliation. I’d love to see someone try it.
Chemiotics II 