Amyloid and Prions—Co-Conspirators in Disease?

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

Comments

  1. The observation that the pathogenesis of neurodegeneration in an animal model of AD is accelerated by prion infection (and vice versa) is very interesting, and the authors consider three possible mechanisms that could underlie this effect. First, they consider that both agents could independently impair clearance mechanisms resulting in some sort of additivity. Second, a variant of the first, they consider the possibility that each agent could independently damage different cellular targets that would give rise to an exacerbation of either single effect. Finally, they consider a cross-seeding mechanism whereby aggregates of Aβ promote the aggregation of PrP and vice versa. They cite published evidence reporting that similar cross-seeding phenomena have been previously observed in vitro (with different proteins). Cross-seeding has also been inferred from studies of interactions between prions in yeast. Although evidence in this Morales study supports the possibility of cross-seeding between PrP and Aβ in vitro, with pure proteins, the evidence that cross-seeding actually occurs in vivo is very indirect—and the extent to which it contributes to the phenotypic interaction between the mouse models remains speculative. Refreshingly, the authors do not overstate their case for cross-seeding. The observed colocalization of both proteins to the same inclusion bodies, while consistent with a direct interaction required for cross-seeding, is rather weak evidence for direct physical interaction. Proteins can readily be incorporated into the same inclusion bodies without any direct physical interaction (see Rajan et al., 2001). There is clearly a large gap between the in vivo and in vitro data in this paper that still needs to be filled in.

    There is a fourth possibility that should also be considered in thinking about these interesting observations. The type of interaction reported in this paper brings to mind the recent work from the Morimoto lab, which demonstrates, using C. elegans, genetic interactions between unrelated folding-defective and aggregation-prone proteins. They have shown that expression of polyglutamine-containing proteins harboring pathogenic-length, aggregation-prone polyQ tracts elicits a mutant phenotype of temperature-sensitive (ts) alleles of unrelated genes—at permissive temperatures (Gidalevitz et al., 2006). They also report the converse effect—that the presence of ts alleles exacerbates the phenotype of aggregation-prone polyQ proteins. Similar genetic interactions have been reported in worms harboring ALS-linked mutant SOD1 transgenes (Gidalevitz et al., 2009). These interactions can be reconciled in a model whereby aggregation-prone proteins compete with other clients of molecular chaperones that are required to both facilitate protein folding and to suppress protein aggregation. According to this view, it is not the aggregate per se that is toxic to cells. It is, rather, the tendency to aggregate or—more precisely—it is the preoccupation of cells’ anti-aggregation machinery (sometimes referred to as the proteostasis network) with persistently expressed, highly aggregation-prone proteins that ultimately results in a "collapse" of the cells’ proteostasis system.

    References:

    Rajan RS, Illing ME, Bence NF, Kopito RR. Specificity in intracellular protein aggregation and inclusion body formation. Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13060-5. PubMed.

    Gidalevitz T, Ben-Zvi A, Ho KH, Brignull HR, Morimoto RI. Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science. 2006 Mar 10;311(5766):1471-4. PubMed.

    Gidalevitz T, Krupinski T, Garcia S, Morimoto RI. Destabilizing protein polymorphisms in the genetic background direct phenotypic expression of mutant SOD1 toxicity. PLoS Genet. 2009 Mar;5(3):e1000399. PubMed.

    View all comments by Ron Kopito

  2. A number of proteopathies coexist in the aging human brain, but whether these diseases arise independently or in pathogenic concert remains unclear. In this paper, Morales and colleagues present a reasonably compelling argument that aggregated Aβ and PrPSc can cross-seed the misfolding and aggregation of each other in vitro and in an animal model of Aβ amyloidosis, arguing for a closer look at the epidemiology of these two pathologies in humans. Lewy body disease and Alzheimer disease overlap in a significant proportion of cases; might similar cross-talk be operable for prion disease and Alzheimer disease? Evidence for such an interaction in humans remains limited, but Morales and colleagues note several supportive studies. I would add the intriguing case of a 28-year-old man who contracted Creutzfeldt-Jakob disease from a dural graft performed in childhood, and who also had a remarkably heavy load of senile plaques and cerebral β amyloid angiopathy at death at age 28 (see Preusser et al., 2006). Though it is possible that the Aβ lesions arose independently in this instance, for example, as a result of the trauma to the brain, the findings of Morales and colleagues suggest that a potential pathogenic interaction of PrP and Aβ should also be considered. More studies, both in humans and models, clearly are needed.

    On a technical note, it would be useful to know the sex of the mice used in the Morales study. Female Tg2576 mice develop more and earlier Aβ deposition than do males, so an imbalance of males and females in the PrPSc-treated group and the control group could yield spurious differences. It will also be interesting in future studies to examine the effects of seeding with Aβ-rich extracts in PrP-transgenic mice. As the authors note, there are numerous mechanistic questions yet to be addressed, but this nice paper should stimulate further experiments in the rapidly evolving field of protein conformational diseases.

    References:

    Preusser M, Ströbel T, Gelpi E, Eiler M, Broessner G, Schmutzhard E, Budka H. Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting. J Neurol Neurosurg Psychiatry. 2006 Mar;77(3):413-6. PubMed.

    View all comments by Lary Walker

  3. I agree with the comments posted by Ron Kopito and Lary Walker. I would add a couple of additional caveats. The in vivo work did not involve large numbers of animals, and the differences in survival rates could potentially be influenced by small sample size (in addition to gender, as Lary mentioned). Likewise, the inoculation protocol did not really include the best negative controls, which would be either brain lysates of sick mice depleted of prion protein, or brain lysates from animals that express PrP, but have not yet developed pathology. The in vitro elements of the paper are crucial to determining whether PrP can directly seed Aβ aggregation. Along those lines, it would be very nice to know whether brain lysates exhibit seeding capacity that is dependent on either Aβ or PrP aggregates within the lysate. At the end of the day, this paper provides a lot of exciting food for thought, and, along with other papers that show cross-seeding phenomena in neurodegeneration, should inspire much further experimentation.

    View all comments by Marc Diamond

  4. A recent study by Ghoshal and her colleagues may be of interest here. In this study, the authors reported that numerous Aβ plaques were co-distributed with spongiform degeneration.

    References:

    Ghoshal N, Cali I, Perrin RJ, Josephson SA, Sun N, Gambetti P, Morris JC. Codistribution of amyloid beta plaques and spongiform degeneration in familial Creutzfeldt-Jakob disease with the E200K-129M haplotype. Arch Neurol. 2009 Oct;66(10):1240-6. PubMed.

    View all comments by Jungsu Kim

  5. The discussion about pathogenic interactions between different amyloidogenic proteins and their aggregates should also consider the possibility that one of these proteins might play a special role in amyloidopathic degenerative diseases and act as a pivotal amplifier of amyloid toxicity. Aβ has been shown to interact with aggregates of several other amyloidogenic proteins, and those aggregates might develop some of their effects through interaction with Aβ and mechanisms of Aβ toxicity, in particular, via the neurotrophin receptor p75 (see the Aβ-crosslinker-hypothesis). These mechanisms may be common to many amyloidopathic degenerative diseases, and partly account for the observed blending of such diseases.

    View all comments by Rudolf Bloechl

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References

News Citations

  1. Prion Protein Keeps β-secretase in Check
  2. Model Shows Oligomers Impair Memory, Questions Role of Prion Protein
  3. Keystone: Partners in Crime—Do Aβ and Prion Protein Pummel Plasticity?
  4. Aβ the Bad Apple? Seeding and Propagating Amyloidosis
  5. Traveling Tau—A New Paradigm for Tau- and Other Proteinopathies?
  6. Guilt by Association?—Aβ, α-Synuclein Make Mixed Oligomers
  7. Aβ Abets α-Synuclein
  8. Synuclein Surprise: Toxicity Linked to Aβ, Plaques?

Paper Citations

  1. Parkin ET, Watt NT, Hussain I, Eckman EA, Eckman CB, Manson JC, Baybutt HN, Turner AJ, Hooper NM. Cellular prion protein regulates beta-secretase cleavage of the Alzheimer's amyloid precursor protein. Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11062-7. PubMed.
  2. Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G. Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2295-300. PubMed.
  3. Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009 Feb 26;457(7233):1128-32. PubMed.
  4. Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, Roth K, Aguzzi A, Staufenbiel M, Walker LC, Jucker M. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12926-31. PubMed.
  5. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. PubMed.
  6. Tsigelny IF, Crews L, Desplats P, Shaked GM, Sharikov Y, Mizuno H, Spencer B, Rockenstein E, Trejo M, Platoshyn O, Yuan JX, Masliah E. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PLoS One. 2008;3(9):e3135. PubMed.
  7. Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, Mucke L. beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12245-50. Epub 2001 Sep 25 PubMed.
  8. Gallardo G, Schlüter OM, Südhof TC. A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and Abeta peptides. Nat Neurosci. 2008 Mar;11(3):301-8. PubMed.

Further Reading

Primary Papers

  1. 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. J Neurosci. 2010 Mar 31;30(13):4528-35. PubMed.

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