The Contribution of Lysosomal Dysfunction to Alzheimer's Disease

It is always pleasant to see portions of the mainstream research community come around to working seriously on parts of the SENS agenda for rejuvenation research, even if they are the better part of 20 years too late to the party. Here, the link is made between lysosomal dysfunction and aspects of Alzheimer's disease. Lysosomes are the recycling units of the cell, organelles packed with enzymes capable of digesting near everything that needs to be dismantled into component parts, be that damaged cell components, metabolic waste, or excess proteins. Unfortunately "near everything" is not the same as "everything", and lysosomes in long-lived cells, such as those of the brain, become cluttered with hardy metabolic byproducts. As a result the whole process of cellular maintenance falters, and cells become damaged and dysfunctional.

The SENS approach to the dealing with this problem is to deliver new enzymes to the lysosome, each capable of breaking down one or more of the problem compounds, tackled in some order of importance. For example, LysoClear is a startup biotech company developing a method of clearing A2E, resulting from earlier research at the Methuselah Foundation and SENS Research Foundation. There are, unfortunately, all too few other programs of this sort at an advanced stage. Perhaps linking lysosomal dysfunction to the big budgets focused on Alzheimer's disease will help to address that problem.

Plaques and tangles have so far been the focus of attention in Alzheimer's disease. Plaques, deposits of a protein fragment called beta-amyloid, look like clumps in the spaces between neurons. Tangles, twisted fibers of tau, another protein, look like bundles of fibers that build up inside cells. "The dominant theory based on beta-amyloid buildup has been around for decades, and dozens of clinical trials based on that theory have been attempted, but all have failed. In addition to plaques, lysosomal storage is observed in brains of people who have Alzheimer's disease. Neurons - fragile cells that do not undergo cell division - are susceptible to lysosomal problems, specifically, lysosomal storage, which we report is a likely cause of Alzheimer's disease."

An organelle within the cell, the lysosome serves as the cell's trashcan. Old proteins and lipids get sent to the lysosome to be broken down to their building blocks, which are then shipped back out to the cell to be built into new proteins and lipids. To maintain functionality, the synthesis of proteins is balanced by the degradation of proteins. The lysosome, however, has a weakness: If what enters does not get broken down into little pieces, then those pieces also can't leave the lysosome. The cell decides the lysosome is not working and "stores" it, meaning the cell pushes the lysosome to the side and proceeds to make a new one. If the new lysosome also fails, the process is repeated, resulting in lysosome storage.

"The brains of people who have lysosomal storage disorder, another well-studied disease, and the brains of people who have Alzheimer's disease are similar in terms of lysosomal storage. But lysosomal storage disorder symptoms show up within a few weeks after birth and are often fatal within a couple of years. Alzheimer's disease occurs much later in life. The time frames are, therefore, very different." Researchers posit that long-lived proteins, including beta-amyloid and tau, can undergo spontaneous modifications that can make them undigestible by the lysosomes. The changes occur in the fundamental structure of the amino acids that make up the proteins and are the equivalent of flipping the handedness of the amino acids, with amino acids spontaneously acquiring the mirror images of their original structures.

"Enzymes that ordinarily break down the protein are then not able to do so because they are unable to latch onto the protein. It's like trying to fit a left-handed glove on your right hand. We show in our paper that this structural modification can happen in beta-amyloid and tau, proteins relevant to Alzheimer's disease. These proteins undergo this chemistry that is almost invisible, which may explain why researchers have not paid attention to it. It's been long known that these modifications happen in long-lived proteins, but no one has ever looked at whether these modifications could prevent the lysosomes from being able to break down the proteins. One way to prevent this would be to recycle the proteins so that they are not sitting around long enough to go through these chemical modifications."


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