A new kid on the Alzheimer’s block

There’s a new kid on the Alzheimer’s block, and it may explain why the huge sums thrown at beta-secretase inhibitors by big pharma has been such an abject failure. First, a lot of technical background.

The APP (for amyloid precursor protein) contains anywhere from 563 to 770 amino acids in 5 distinct transcripts made by alternate splicing of the single gene. The 3 main forms contain 695, 751 and 770 amino acids. The 695 amino acid form is found only in brain and peripheral nerve where it predominates, while the transcripts containing 751 and 770 amino acids are found everywhere but predominate in other tissues. The A4 peptides (Abeta peptides) which are the major components of the Alzheimer senile plaque are derived from from the carboxy terminal end of APP (beginning at amino acid #597 ) and contain only 39 – 43 amino acids. About 1/3 of the 39 – 43 amino acid amyloid beta peptide (A beta peptide) is found within the transmembrane segment of APP the other two thirds being found just outside the membrane.  So to get A beta peptides the APP must be cut (more than once) at its carboy terminal end.

For Abetaxx (xx between 39 and 43) to be formed, cleavage must occur outside the membrane in which APP is embedded by beta secretase. This produces a soluble extracellular fragment, with the rest embedded in the membrane (this is called C99). Then gamma secretase (another enzyme) cleaves C99 within the membrane forming the Abeta peptides, which constitute much of the senile plaque of Alzheimer’s disease.

Alpha secretase (yet another enzyme) also cleaves the APP in its carboxy terminal extramembranous part, but does so closer to the membrane, so that part of the protein which would form the aBeta peptide is removed.

R. Scheckman personal communication (2012) — The Abeta peptide is appears to be cleaved by gamma secretase from the fragment generated by beta secretase. However, this happens well inside the cell in the last station of the Golgi apparatus. Then Abeta is swept out of the cell by the secretory pathway. So all this happens INSIDE the cell, rather than at the neuron’s extracellular membrane (which is what I thought).

Remarkably it is very difficult (for me at least) to find out just at what amino acids of the amyloid precursor protein(s) the 3 secretases (alpha, beta, gamma) cleave.

[ Nature vol. 526 pp. 443 – 447 ’15 ] describes a totally new kid on the block, which (if replicated) should make us rethink everything we thought we knew about the amyloid precursor protein and the Abeta peptide. Another set of carboxy terminal fragments (CTFs) called CTFneta is formed from the amyloid precurosr protein (APP). Formation is mediated (in part) by MT5-MMP, a matrix metalloprotease. (In grad school neta is how we pronounced the Greek letter eta, which looks like a script N). The authors call the enzymatic activity forming them neta-secretase (clearly not all the enzymes which do this have been identified at this point). At least the authors tell you where the neta secretases cleave APP695 (between amino acids #504 – #505) . This is amino terminal to the beta and alpha sites (which are at higher amino acid numbers and the gamma site which is at a higher number still).  Alpha and beta secretase then work on CTFneta to produce shorter peptides, called Aneta-alpha, and Aneta-beta.

This isn’t idle chatter as Aneta-alpha, and Aneta-beta are found in the dystrophic neurites in an Alzheimer mouse model (human work is sure to follow). Inhibition of beta secretase activity results in accumulation of CTFneta and Aneta-alpha.

Aneta-alpha itself lowers long term potentiation (LTP) in hippocampal slices (LTP is considered by most to be the best molecular and physiological model we have of learning). As judged by intracellular calcium levels, hippocampal neuronal activity is also inhibited by Aneta-alpha.

What’s fascinating about all this, is that the work possibly explains why the huge amount of money big pharma has spend on beta secretase inhibitors has been such a failure.

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Comments

  • DN  On October 22, 2015 at 2:25 am

    Have you thought much about the life history of Alzheimer’s disease? To me it seems more like puberty than melanoma. It seems a programmed part of the senescence process. Once a hormone threshold is crossed, a soluble factor starts carrying the degenerate-now message to the entire brain simultaneously.

    Like puberty, its occurrence at the second birthday is vanishingly low. Even in bizarre genetic defects it is super-rare. Once it starts, it progresses globally at the same rate everywhere. If it were a simple build up of amyloid-beta, we would run across the occasional four year old child with Alzheimer’s disease in only one hemisphere. You’re the neurologist: does that ever happen? Has there ever been one person whose left hippocampus wasted away at age 15?

    I think the mystery will be cracked by population genetic sequencing. Once we know the upstream mutations that advance and delay the clinical phenotype, then they can actually find usable drug targets. If that’s too expensive, then for heaven’s sake drug companies should do directed mutation studies of APP in rodents. That would point directly to the proteases that affect the dementia phenotype. This stabbing around in the dark with amyloid-beta is an exercise in futility. It would be like working on actin degrading proteases to treat heart failure.

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