Editor's Note: This is part two of a two-part series on new findings in Alzheimer's research. Part one ran in Thursday's issue.
Though it's a bit of a chicken-and-egg question, the status of research favors the idea that amyloid plaques cause Alzheimer's, rather than the other way around; what causes the plaques themselves in the first place, though, is still unclear.
In the Sept. 22, 2006, issue of Science, researchers led by Mathias Jucker, of the University of Tübingen, and Lary Walker, of Atlanta's Emory University showed evidence from animal studies that the same domino process that underlies the generation of clumps of misfolded prion proteins also can jump-start the formation of plaques in Alzheimer's disease.
"The most important implication of the paper is the mechanistic similarity of all these diseases," senior author Walker told BioWorld Today. "Our data suggest that you can corrupt normal proteins by these misshapen disease proteins. And I think that's going to turn out to be true for a whole list of diseases."
By injecting animals that have brains containing high levels of amyloid precursor protein (which is processed into amyloid-beta) with brain extracts from Alzheimer's patients or transgenic mice, the researchers showed that small amounts of misfolded amyloid-beta can initiate the development of plaques. The plaque formation could be prevented either by destroying the misfolded amyloid-beta before injecting the extracts, or by immunizing the recipients.
Jucker, Walker and their colleagues used two different mouse strains for their research: a transgenic expressing human amyloid precursor protein named APP23, and an APP-PS1 strain that also expresses the protein presenilin.
While both strains make mutant amyloid precursor protein, the additional expression of presenilin in the APP-PS1 mouse accelerates the development of pathology. An important finding of the paper, Walker said, was that both host and guest play a role in determining the exact nature of the seeded plaques. APP23 mice and their brain extracts tended to produce more diffuse plaques, while the APP-PS1 mouse plaques are coarser and more dot-like.
Walker noted that the observations do not imply that one model or the other is more clinically relevant: While he said that his "gut feeling" was that APP23 mice produce slightly more human-like plaques, he noted that both models have the cellular reactions typical of Alzheimer's, and at any rate, none of the mice developed true Alzheimer's disease.
"It's hard to extrapolate too far from our mice, since only humans get Alzheimer's," he said.
But the results demonstrated that "when we inject brain extract from one strain into another, the morphology of the resulting plaques depends both on where [the seed protein] is coming from and where it's going."
The paper did not address the question of where the initial seed protein comes from when it's not coming out of a researcher's syringe. Walker said that "we can't rule out environmental factors," but there's no need for a public health panic - even the transmission of prion diseases to humans is "extraordinarily rare" and even "if Alzheimer's were to be transmissible, the same would be true." Transmission of Alzheimer's would probably be even rarer than transmission of Creutzfeldt-Jacob disease, because while prion proteins are known to piggyback on the immune system to reach the brain, there is no evidence that amyloid-beta protein can do the same.
Walker's hunch is that even if transmitted cases of Alzheimer's disease do exist, their numbers pale in comparison to self-starter cases.
"Now that we know that this is a seedable process," he said, "one of the most important questions is, 'Where does the seed come from?' And I don't know. I can speculate, and my speculation is that it usually starts as a chance process - bad luck, if you will, or simply that the conditions in the aging brain are favorable to the formation of a seed."
The study authors are from the University of Tuebingen in Germany; the Novartis Institutes for Biomedical Research and the University of Basel in Switzerland; University College Dublin in Ireland; New York University and Atlanta's Emory University.