Fight Aging!

The molecular biology of Alzheimer's disease is enormously complex, and efforts to better understand it have spurred a great deal of the broader work that has taken place to decipher and catalog the biology of the brain over the past twenty years. Even given the rapid improvements in biotechnology taking place over that time and the large-scale funding pouring into Alzheimer's research, the present state of knowledge is still incomplete, a work in progress.

Alzheimer's is a disease of protein aggregation, its progression and severity associated with the formation of deposits of misfolded proteins known as amyloid and neurofibillary tangles (NFTs). It isn't just this, however, that is the crux of the condition, but rather the fine details of how amyloid and NFTs form and interact with their surroundings. In those fine details lie mechanisms that cause cellular dysfunction and death, and that is still a very active area of research. These mechanisms, in play once there are significant amounts of misfolded protein in the brain, are completely separate from the question of how an older individual gets to that point, however. Levels of misfolded proteins are dynamic over short time frames, and Alzheimer's has the look of a condition that develops due to a slow failure of the mechanisms that clear metabolic waste from brain fluids. There is as much debate in the research community over those root causes as there is over the precise details of the mechanisms that disrupt brain function in the later stages of the condition. Is it damage to the choroid plexus that filters cerebrospinal fluid, is it declining function in small vessels that drain that fluid, or something entirely different? These details are all open for further evidence, discussion, and argument.

The main thrust of Alzheimer's research when it comes to building prospective treatments remains the clearance of amyloid, such as via immunotherapies. It has been a long haul since this strategy was first proposed, however, and still there is no practical treatment to show for all the effort expended. This is despite a number of attempts that made it all the way to clinical trials. As is often the case, protracted delay in reaching treatment milestones has led to a certain degree of discontent and rebellion against the amyloid clearance consensus, and a healthy diversity of alternative approaches are in the works. This I think is for the better whether or not clearance of amyloid falters in the end, or simply turns out - like everything in biology - to be much harder and more complex than anticipated.

The research reported below is, I think, I good illustration of some of the complexity involved in the biochemistry of Alzheimer's disease. On the one hand this complexity makes everything harder, and on the other hand it offers a plethora of points at which well designed drugs might interfere with the disease process. Still, I would prefer to see work on repair of clearance mechanisms rather than work on sabotaging the disease process that becomes important once there is a lot of amyloid present. It should always be better - more efficient, more comprehensive - to strike at the root causes rather than even very effectively neutering later stages of the cascade of consequences.

Molecular inhibitor breaks cycle that leads to Alzheimer's

Alzheimer's disease is one of a number of conditions caused by naturally occurring protein molecules folding into the wrong shape and then sticking together - or nucleating - with other proteins to create thin filamentous structures called amyloid fibrils. Proteins perform important functions in the body by folding into a particular shape, but sometimes they can misfold, potentially kick-starting this deadly process. Recent research has however suggested a second critical step in the disease's development. After amyloid fibrils first form from misfolded proteins, they help other proteins which come into contact with them to misfold and form small clusters, called oligomers. These oligomers are highly toxic to nerve cells and are now thought to be responsible for the devastating effects of Alzheimer's disease.

This second stage, known as secondary nucleation, sets off a chain reaction which creates many more toxic oligomers, and ultimately amyloid fibrils, generating the toxic effects that eventually manifest themselves as Alzheimer's. Without the secondary nucleation process, single molecules would have to misfold and form toxic clusters unaided, which is a much slower and far less devastating process. By studying the molecular processes by which each of these steps takes effect, the research team assembled a wealth of data that enabled them to model not only what happens during the progression of Alzheimer's disease, but also what might happen if one stage in the process was somehow switched off. Researchers were able to identify a molecular chaperone, Brichos, that effectively inhibits secondary nucleation.

The research team then carried out further tests in which living mouse brain tissue was exposed to amyloid-beta, the specific protein that forms the amyloid fibrils in Alzheimer's disease. Allowing the amyloid-beta to misfold and form amyloids increased toxicity in the tissue significantly. When this happened in the presence of the molecular chaperone, however, amyloid fibrils still formed but the toxicity did not develop in the brain tissue, confirming that the molecule had suppressed the chain reaction from secondary nucleation that feeds the catastrophic production of oligomers leading to Alzheimer's disease.

A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers

Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the ​amyloid-β peptide (​Aβ42). Recent studies have revealed that once ​Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human ​Aβ42 toxicity.

We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.