Malin Sandberg et al. show that the buildup of infectious prion particles (PrPsc) is distinct from the generation of toxicity, which then presumably is conferred by another PrP species (which we can call toxic PrP). There are clearly possibilities for mechanistic analogies in AD and other neurodegenerative diseases.

The authors measure PrPsc levels in mice with different PrP expression after inoculating these with PrPsc. Mice that do not express PrP do not produce PrPsc, as expected. However, three other mice in which relative PrP expression ratios of 0.5 to 1 to 8, that is, over a range of a factor of 16, all build up PrPsc with similar rates and up to the same plateau concentration.

At this point, some other process kicks in, which logically ought to be production of toxic PrP. This time, mice living with plateau concentrations of PrPsc become sick and die following plateau incubation times that are inversely proportional to the rates of PrP expression! In the language of physical chemistry, this is first-order kinetics in which the rate of toxic PrP generation is...  Read more

Malin Sandberg et al. show that the buildup of infectious prion particles (PrPsc) is distinct from the generation of toxicity, which then presumably is conferred by another PrP species (which we can call toxic PrP). There are clearly possibilities for mechanistic analogies in AD and other neurodegenerative diseases.

The authors measure PrPsc levels in mice with different PrP expression after inoculating these with PrPsc. Mice that do not express PrP do not produce PrPsc, as expected. However, three other mice in which relative PrP expression ratios of 0.5 to 1 to 8, that is, over a range of a factor of 16, all build up PrPsc with similar rates and up to the same plateau concentration.

At this point, some other process kicks in, which logically ought to be production of toxic PrP. This time, mice living with plateau concentrations of PrPsc become sick and die following plateau incubation times that are inversely proportional to the rates of PrP expression! In the language of physical chemistry, this is first-order kinetics in which the rate of toxic PrP generation is directly proportional to PrP concentration (given that all mice die at the same levels of toxic PrP). Hence, one can arrive at the following conclusions: 1) the production of infectious PrPsc and toxic PrP are separate processes; 2) there is some mechanism that limits infectious PrPsc to a maximum concentration; and possibly 3) toxic PrP starts to be generated when PrPsc reaches the maximum concentration. The evidence for number 3 is indirect since the levels of toxic PrP cannot be measured directly.

The study leaves a few open questions that do not really cloud the story and that eventually may be answered. First, as pointed out in a comment by Reed Wickner in the same issue of Nature, the authors assume that the same amount of toxic PrP kills all types of mice. This might not be the case. Second, it is not completely clear exactly when toxic PrP starts to appear. Third, it would be nice to eventually find out how toxic effects are generated or mediated.

Still, the possibility that similar or identical mechanisms operate in AD and other neurodegenerative diseases is intriguing. For instance, what about the long "plateau time" during which amyloid-β plaques accumulate before onset of AD, or even MCI symptoms? Are the plaques analogous to PrPsc and propagate from some kind of infectious seed? Is the delay between plaque appearance and onset of symptoms a period during which toxic Aβ species accumulate at a rate which is proportional to Aβ production? Is there, then, a critical concentration of toxic Aβ that triggers disease? Why, then, is this concentration so critical? Is it perhaps related to the initiation of tau pathology? How do we address these questions?

These and related issues have been food for much thought already, and the new results on PrP will fuel the discussion.

View all comments by Torleif Hard