Our niece in Hawaii, Denise, recently shared with us an article from SciTechDaily about a breakthrough in understanding how beta amyloid is generated in the brain. On the one hand, the research provides an intriguing idea that may point to new treatments for Alzheimer's disease. On the other hand, it relies on the amyloid hypothesis for a rationale for how the discovery could lead to the new treatments. As we discussed in Beating the Dementia Monster, there are reasons to doubt the centrality of beta amyloid in the disease process.
If you read Beating the Dementia Monster (and read other blog posts here), you know that the amyloid precursor protein (APP) is cut a couple of times to form different peptides -- strings of amino acids that don't qualify as proteins any more. Some of these are amyloids. Depending on how the protein is cut, the resulting peptides may be either innocuous or harmful. The harmful ones clump onto brain cells, impeding the movement of information between cells and possibly killing them.
Common sense says we should try to stop the production of amyloids and/or clean amyloids out of the brain to treat the disease. As we've said before, Aduhelm and other treatments clean the brain of amyloid. But improved cognition has been hard to detect. So some (like me) are skeptical of the central role of beta amyloid in the disease process. Yes it forms, and yes it kills brain cells, but is that important to the disease process? Will disrupting beta amyloid formation stop the disease? Problems with getting Aduhelm to significantly improve cognition suggests to me that gum disease and virus infection may be richer areas of investigation.
Nevertheless, it's important to understand how beta amyloid forms because it may provide additional insight into the disease. We definitely don't understand how the disease unfolds as well as we need to.
The SciTechDaily article draws from research performed at Massachusetts General Hospital and published in the journal Cell Reports. The research contributes to a clearer understanding of the process by which the APP is cut.
We discussed before the endoplasmic reticulum which is an organelle (kind of like an organ within the cell) that processes lipids (another name for fats) and cholesterol. It also hosts the ribosomes where polypeptide chains are assembled from amino acids and folded into proteins. It was known that this is where APP is cut, but the cutting process wasn't well understood.
What the new research brings to the table is a better understanding of how an APP molecule is prepared for cutting. During the preparation time, it's transported in a fatty sac, called a lipid raft. The research points to the possibility that preventing the construction of lipid rafts might short-circuit the cutting process, and this might prevent the cutting of APP molecules and therefore prevent the production of beta amyloid. Gene therapy or a drug that blocks a key protein called the "sigma-1 receptor," will decrease cutting of APP molecules in nerve cells and lower beta amyloid production. As noted in the SciTechDaily article, several possibilities revealed by this research are being pursued.
We'll see where this all goes -- and I hope it goes somewhere helpful. It may be that stopping the production of beta amyloid (rather than just cleaning it out of the brain) may actually slow or stop progress of the disease better than the treatments that have been proposed and/or applied so far -- like Aduhelm. Or maybe simply learning more about how the disease unfolds will lead us to a more fundamental Achilles heel in the disease.
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