What can mad cow disease teach us about Alzheimer’s

If you’re old enough, you might remember hearing about the mad cow disease crisis in Europe at the end of the 90s. This disease was caused by something called prions, aggregates of misfolded proteins that become infectious. For a protein aggregate to be considered as prion it is necessary that the interactions among its molecules are so strong that the aggregation is irreversible and resists the cell’s clearing mechanisms (like the proteasome) and, most importantly, that they propagate from cell to cell accumulating more peptides to the misfolded aggregate and extending the damage to otherwise healthy cells.

It looks like a normal cow, but actually it is not. It suffers from Creutzfeldt–Jakob disease and as a result cannot stand on its feet. In the 90s there were thousands of them

This disease, which was characterized by strong neurological symptoms, hence the name, might have more in common with other neurodegenerative diseases like Alzheimer’s, Hungtington’s or Parkinson’s as anyone may have thought. Not only because of the presence of protein aggregates, which is a well-known characteristic of these diseases, but because the behaviour of the aggregates might resemble that of prions. If that were the case, aiming at limiting the prion-like infectious cycle might limit the extent of the neurodegeneration.

But let’s review the evidence behind the so-called prion hypothesis in neurodegenerative diseases. First, a certain stereotypical pattern of progression has been described for each of the 3 aforementioned diseases, where certain brain areas, like the olfactory bulb, would be found to be affected earlier than others, even before clear symptomatology arises. For instance, olfactory dysfunction is considered an early sign of Parkinson’s. Naturally, this pattern brings about the question of the mechanism of transmission, which could be anterograde (moving away from the neuron) or retrograde (if directed towards it) along the axonal connections.  Multidisciplinary evidence, from in vitro experiments, transgenic models and postmortem analysis has shown, that at least for α-synuclein, the protein responsible for the aggregates in Parkinson’s, intercellular tranference is possible.  For example, in culture the addition of green-labelled α-synuclein oligomers (small protein aggregates) could induce the formation of dual color inclusion bodies (big size aggregates) in cells where the native α-synuclein protein was labelled in red, suggesting the internalized oligomers could act as a seed for aggregation. If these oligomers were to be transfered axonally from cell to cell, that would explain the pattern of progresion of affected brain areas. The aggregation pathology in Alzheimer’s is more complex, since it involves 2 types of aggregates and 2 differents proteins. The extracellular aggregates, known as amyloid plaques, are formed by accumulation of amyloid-β while intracellularly, it is the tau protein which forms neurofibrilary tangles. Tau is more similar to α-synuclein, because of its lack of native structure, and therefore the one that has the greater potential to act as a prion-like protein. In fact, experiments have shown that while amyloid-β oligomers can act as seed for new aggregation. However, this seeding process does not involve intracellular transmission. In contrast, experiments with small aggregates of tau protein have shown its capability to access “healthy” neurons and induce the aggregation of the native tau in those cells. In conclusion, it seems that tau and α-synuclein have the potential to act as the transmission vectors for the aggregation disease, and therefore propagate the disease.

Prion replication cycle. Shown for PrPc, an actual prion. It is postulated that a similar process would occur in aggregation diseases such as Alzheimer’s. Credit: Joannamasel at English Wikipedia

Although the exact mechanisms of oligomer exchange between cells are unknown, both at the level of oligomer exit from affected cells and the uptake by neighbouring cells, it seems clear based on all the above evidence that a prion-like mechanism might be involved in progression of neurodegeneration. Given these are aging-associated diseases, it would be possible that after an “incubation” period, where protein aggregates begin accumulating, after a certain tipping point, oligomers would be released by “sick” cells and internalized by neighbouring “healthy” cells spreading protein aggregation and hence, the disease.

If such a mechanism would be confirmed to play a role in disease progression, a new possible therapeutic agent could be developed targeting determining steps of the process. But for that, I am afraid we will have to wait, but hopefully not as long as mad cow disease was in the news (1986-98 in the UK).

 

Brundin P, Melki R, Kopito R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol. 2010 Apr;11(4):301-7. doi: 10.1038/nrm2873.

Further reading:

Cicchetti, F. et al. Neural transplants in patients with Huntington’s disease undergo disease-like neuronal degeneration. Proc. Natl Acad. Sci. USA 106, 12483–12488 (2009).

Frost, B., Jacks, R. & Diamond, M. Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem. 284, 12845–12852 (2009).

Danzer, K. M., Krebs, S. K., Wolff, M., Birk, G. & Hengerer, B. Seeding induced by α-synuclein oligomers provides evidence for spreading of α-synuclein pathology. J. Neurochem. 111, 192–203 (2009).

 

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