Are Proteins “Toxic” in Neurodegenerative Diseases?

By: Drs. Andrea Sturchio and Alberto J. Espay

The “amyloid cascade” hypothesis has been for decades the guiding principle in our attempts to find treatments to slow Alzheimer’s disease. Similarly for just about all other neurodegenerative disorders, the premise is that certain proteins, upon losing their normal shape when exposed to different triggers, become toxic by virtue of aggregation into amyloids and a presumed ability to replicate and propagate through the brain. Such spread of amyloids slowly “kill” the neurons in a manner similar to that of viruses.

This hypothesis, however, has three key shortcomings:

1) Lack of clinical correlation: more amyloid does not equal more neurons dying.

2) Lack of support from anti-amyloid treatments: all clinical trials have been negative.

3) Lack of a precise mechanism: replication like a virus without a biological machinery to do so.

Poor clinical correlation

The presence of amyloid aggregates is common in healthy individuals without any neurological symptoms. How can a supposedly toxic substance be present in so many healthy subjects for so many years? This is evident if we look at imaging data that allows us to study the presence of these aggregates in the brains of living people. Up to 30% of individuals with what is considered enough of these aggregates to cause disease live perfectly healthy lives without any signs of cognitive impairments. (see image above). … very high for something considered toxic, and the cause of disease!

Negative clinical trials

To date, all clinical trials aimed at reducing amyloid aggregates have failed. This was despite the fact that at least 67% of them were confirmed to do exactly what they were supposed to, namely markedly reduce the amount of these brain aggregates. If these amyloids were in fact as toxic as the hypothesis claims, the clinical trials should have shown some benefit. In fact, in nearly 40% of them, individuals who were given the anti-amyloid treatments worsen their symptoms and in many of these cases, their brains exhibited some shrinking.

No mechanism of “replication”

The first paper in which the hypothesis of aggregation and virus-like spread of proteins was proposed dates back to 1982. Yet, to date, a mechanism of such spread remains unclear, though a popular candidate was inspired by the most important discovery of the 20th century: deoxyribonucleic acid (DNA), the molecule that provides precise instructions to make proteins. DNA has the ability to replicate itself, thanks to the presence of a precise code and dedicated machinery. But DNA is very different from proteins. While DNA replicates from a code, the proteins from which it is constructed don’t have such a code to replicate themselves. As such, the observed spread of proteins is not fueled by “replication” but, rather, polymerization, a process similar to crystallization, exemplified most often by the transformation of water into ice. 

An important property of proteins, one of the pillars of biology, is that they need to have a precise shape to work; when that shape is lost, they cannot carry out their normal function. The loss of their function as they clump into amyloids may be the true “toxin,” facilitating the process of neurons dying, or neurodegeneration. This concept in effect turns the amyloid hypothesis on its head: the problem may not be (at least early on) from an increase in proteins in their aggregated, crystallized state but a corresponding decrease of those proteins in their normal state, precluding their ability to fulfill many vital tasks for the brain to function normally.

What makes proteins go from their normal state (like water) to their amyloid state (like ice)? Proteins may just turn into amyloid because they are genetically unstable, such as in the case of mutations in the amyloid generating proteins. The most common reason is probably the exposure to external triggers, such as viruses. This knowledge allows charting two parallel strategies to slow or stop the progression of neurodegenerative diseases: 1) increase the level of the protein being lost during the aggregation process; and 2) eliminate the trigger turning normal proteins into amyloid. The former would be a therapy suitable for most patients, as a form of “rescue medicine;” the latter specific for each person, a veritable expression of “precision medicine.” This dual approach, a paradigm shift from decades of allegiance to the “amyloid cascade” hypothesis, has the potential to form the new pillars of progress in the fight against neurodegenerative diseases.

Featured image by Susan Landau and William Jagust (source)

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