5 April 2010. Many neurodegenerative diseases involve a common pattern of protein misfolding, aggregation, and toxicity. Though the identity of the actual polypeptide varies for each disease, the outcome converges on a similar bad end for neurons. But how much do the different proteins, and their deadly pathways, have in common? To address the question, Claudio Soto and colleagues at the University of Texas Medical School, Houston, looked at a pair that cause distinctly different diseases, and found that a propensity for misfolding can be enough to forge a pathologic partnership.
The proteins in question are the β amyloid of Alzheimer disease (AD) and the prion protein that causes transmissible spongiform encephalopathy, the only protein misfolding disease known to be contagious in people. Soto and colleagues injected infective prions into an AD mouse model, and found an exacerbation of pathology and an accelerated onset of disease. In addition, each protein cross-seeded aggregation of the other in vitro. The study, published in the March 31 Journal of Neuroscience, has implications for understanding protein folding diseases in general, and raises the question of whether protein misfolds may be more widely transmissible than we think.
To look at interaction between Aβ and prions, first author Rodrigo Morales dosed young (45-day-old) or old (365-day-old) Tg2576 mice with infectious prions by intraperitoneal injection, and compared their progress to uninoculated transgenics or inoculated wild-type mice. He found that prion disease progressed to clinical symptoms and death much faster in the Tg2576 mice compared to wild-type. Mice injected at older ages, when AD pathology was apparent, developed disease the fastest. The animals showed the characteristic spongiform degeneration of prion disease and accumulation of the misfolded prion protein, neither of which were present in uninfected Tg2576 mice. While the presence of Aβ did not seem to affect the extent of prion-driven spongiform degeneration, it did increase the levels of prions that could be measured in brain tissue. Likewise, the presence of prions increased brain inflammation and Aβ deposition. The authors conclude that the presence of prions leads to a dramatic acceleration in the misfolding, aggregation, and cerebral accumulation of Aβ, and vice versa.
The researchers considered three explanations for the exacerbation of amyloid pathology by the prions. First, the prions might cause an overload of the clearance mechanisms for misfolded protein that were already strained by Aβ accumulation. Alternatively, nerve cells stressed by one protein might be more sensitive to a second insult. Or, direct interaction between the two proteins might lead to accelerated protein misfolding. In support of the latter possibility, the researchers found prions in amyloid deposits in the injected transgenic mice, a situation they did not find in animals with only amyloid plaques or prion disease. When they looked at protein aggregation in vitro, seeding Aβ preparations with prions produced an acceleration of aggregation, and amyloid fibrils accelerated the appearance of misfolded prion proteins. It is not shown whether the fibril-induced prions are infectious, but the results suggest that the two proteins have the potential to mutually accelerate each other’s misfolding and aggregation.
The normal cellular prion protein was recently implicated in AD, where it appears to regulate β-cleavage of APP (see ARF related news story on Parkin et al., 2007) and act as a receptor for Aβ oligomers in cells (see ARF related news story on Balducci et al., 2010 and ARF related news story on Laurén et al., 2009). In addition, there are scattered reports of co-occurring Aβ and prion pathology in human disease, but just how common the situation might be is unknown. One reason for that is that Alzheimer’s researchers have not really looked at prion proteins, Soto told ARF. “People think prion diseases are a different group because they are rare and because they are infectious and Alzheimer’s is not,” he said. That is changing, though, with some researchers pursuing the idea that misfolding of Aβ and tau may follow the same principles as prion propagation by spreading from protein to protein, cell to cell, and region to region in the brain (see ARF related news story on Eisele et al., 2009 and ARF related news story on Clavaguera et al., 2009). Because of that, Soto said, there will be more interest in looking at prion pathology in AD going forward.
The coexistence of multiple misfolded proteins appears to be the rule in Alzheimer disease and other neurodegenerative conditions. In AD, Aβ and tau form different pathological aggregates, and sometimes α-synuclein appears as well.
There is evidence for cross-seeding of Aβ and α-synuclein (see ARF related news story on Tsigelny et al., 2008), and the two proteins that have been known for some time to interact pathologically in mouse models (see ARF related news story on Masliah et al., 2001 and ARF related news story on Gallardo et al., 2008). However, the possibility that Aβ might cross-seed with a protein from a transmissible disease raises the intriguing question of whether there could be transmissible forms of AD, PD, and similar neurodegenerative diseases. Last year, Mathias Jucker, University of Tubingen, Germany, and colleagues published mouse experiments showing transmission of Aβ pathology by direct injection of amyloid into brain (Eisele et al., 2009). The big question is whether such transmission can occur in a natural setting, as it does in prion diseases. One possibility is transmission via blood transfusion, Soto said, since oligomeric Aβ has been found in the circulation. However, blood-borne transmission of Aβ pathology was not observed in the Jucker study.
The results suggest that the presence of one protein misfolding disease may be a risk factor for another, either by cross-seeding or by other mechanisms. One example that Soto is interested in is type 2 diabetes, where the IAPP (islet amyloid polypeptide, also known as amylin) forms plaques in pancreatic β cells, which may contribute to the progress of that disease. Could the presence of pancreatic amyloid help explain the higher risk of AD among diabetics? Or alternatively, could Aβ explain the increased risk of diabetes among people with AD? Those are questions that his lab is actively investigating now.—Pat McCaffrey.
Morales R, Estrada LD, Diaz-Espinoza R, Morales-Scheihing D, Jara MC, Castilla J, Soto C. Molecular cross talk between misfolded proteins in animal models of Alzheimer’s and prion diseases. 2010 March 31. J. Neurosci. 30(13):4528-4535. Abstract