In Alzheimer’s and other brain diseases, normal proteins adopt strange conformations that make them clump together and cause trouble for neurons, perhaps even killing them. Two new studies provide insight into the origins of this process. In an October 4 Molecular Psychiatry paper, researchers led by Claudio Soto at the University of Texas Medical School, Houston, report that injecting human AD brain extract brings on brain amyloid deposition in transgenic mice that do not normally develop plaques. The results add to prior data raising the specter of prion-like transmission for some sporadic AD cases. And in last week’s Journal of Neuroscience, Mathias Jucker of the University of Tübingen, Germany, and colleagues propose that the most robust “seeds” of cerebral amyloidosis may be soluble. If these perilous Aβ forms could be identified in bodily fluids, they could potentially serve as diagnostic AD biomarkers or targets for early intervention.

Unlike in classic infectious diseases, the transmissible agents in prion disorders such as bovine spongiform encephalopathy (BSE, aka “mad cow disease”) and Creutzfeldt-Jakob disease are simply normal proteins that change shape to become destructive. AD’s amyloid-β peptides also exhibit this uncanny property, prompting Soto and others to explore whether AD pathology can be triggered in prion-like fashion—that is, by inoculation with the misshapen protein. Prior work from Jucker’s and Lary Walker’s group at Emory University, Atlanta, Georgia, showed that postmortem AD brain extract can hasten amyloid deposition not only when injected into the brains of AD transgenic mice (see ARF related news story on Meyer-Luehmann et al., 2006; Kane et al., 2000), but also when it gets in via the periphery (see ARF related news story on Eisele et al., 2010). However, the host animals in those studies were already predisposed to develop AD pathology because they overexpress mutant amyloid precursor protein (APP); the inoculate simply quickened the process.

In the Molecular Psychiatry study, first author Rodrigo Morales and colleagues wanted to see if they could stimulate Aβ deposition from scratch, that is, in transgenic mice (HuAPPwt) expressing wild-type human APP and showing no evidence of plaques at the ripe age of over 24 months. The researchers gave five-month-old HuAPPwt mice a shot of AD brain extract, or control extract from a young person, into the hippocampus, and checked for Aβ aggregates 285, 450, or 585 days later. As judged by thioflavin S and anti-Aβ antibody (4G8) staining, none of the control mice showed detectable Aβ aggregates, whereas animals receiving AD extract had diffuse Aβ deposits at the first two timepoints and full-blown, ThioS-positive plaques by day 585. The extent of Aβ aggregation and astrogliosis in these mice intensified with age, and showed up in brain areas far from the injection site, suggesting the seeding activity can spread.

While popular press articles tout the findings as evidence that AD could be “contagious” (see CBS News and Fox News coverage), scientists point out that the new and prior studies were done in AD mouse models that do not develop the full spectra of AD symptoms—only Aβ protein aggregates in the brain—even when injected intracerebrally with AD brain extract. “No experiment has yet shown that AD per se can be transmitted in a prion-like fashion,” wrote Walker in an e-mail to ARF. Furthermore, transmission of prion disease to humans is extremely rare, with less than 700 known cases to date, most under extraordinary circumstances such as treatment with contaminated growth hormone from human cadaveric pituitary glands or in the wake of the BSE outbreak in the 1980s and 1990s (Belay and Schonberger, 2005). No case of AD having been transmitted from person to person, or from animal tissue to a person, has ever been described.

Rather, the current paper lends further support to a concept bandied about for some time—the possibility that protein aggregates in prion diseases, AD, and other brain disorders may form and spread by a common molecular mechanism. Walker and Jucker call it “corruptive protein templating” (aka “seeding”), and lay out evidence for this as a “prime mover of the neurodegenerative process” in a forthcoming Annals of Neurology review (currently online as an “accepted article”). Walker also led an ARF Webinar on this topic.

Earlier primate studies suggested that exogenous Aβ protein could trigger cerebral amyloidosis (Baker et al., 1993; Ridley et al., 2006), and Walker has data, recently submitted for publication, showing prion-like induction of Aβ pathology in transgenic rats that express mutant human APP but do not develop plaques or cerebral amyloid angiopathy through 30 months of age (Agca et al., 2008). Evidence for prion-like propagation of protein aggregates is also accumulating for Parkinson’s (see ARF related news story on Desplats et al., 2009; Hansen et al., 2011; Kordower et al., 2011), Huntington’s (see Ren et al., 2009), and amyotrophic lateral sclerosis (Chia et al., 2010; Munch et al., 2011; ARF related news story on Furukawa et al., 2011).

While these studies point to the ability of amyloidogenic proteins to act as seeds, the nature of the seed remains a mystery. In the Journal of Neuroscience paper, Jucker’s team further characterized the Aβ seeding factor in APP transgenic mouse brain. Using four-month-old pre-plaque APP23 transgenic mice as hosts, first author Franziska Langer and colleagues injected their hippocampi with Aβ aggregate-containing extract from aged APP23 brains, and analyzed brain amyloid load in the treated animals four to five months later. They treated the injection material in various ways to correlate its seeding ability with its biochemical properties.

In one set of experiments, the researchers found that proteinase K (PK)-treated extracts could still induce amyloidosis in the host mice, albeit only 55 percent as robustly as untreated inoculate. While this jibes with other work suggesting that increased protease resistance makes misfolded proteins better at seeding, the data also argue that PK-sensitive seeds exist, since PK-treated extract did not trigger amyloid deposition as robustly as non-treated extract.

To examine that possibility, the researchers used ultracentrifugation to spin out the larger aggregates from the aged APP23 extract. When they injected the leftover soluble material into younger APP23 host mice, it was “surprisingly effective at inducing formation of new plaques,” said Walker, a coauthor on the J. Neuroscience paper. Though less than 0.05 percent of the Aβ remained in the supernatant after ultracentrifugation, this soluble fraction accounted for up to 30 percent of the seeding activity and was PK sensitive. Aβ aggregates arising from soluble seeds tended to be smaller and more uniformly distributed, relative to Aβ assemblies induced by the insoluble fraction.

Scientists called this a nice paper with interesting results and carefully executed experiments. However, Sylvain Lesne of the University of Minnesota, Minneapolis, would like to have seen a more rigorous biochemical characterization of the soluble and insoluble fractions. “Only monomeric Aβ levels are reported,” Lesne wrote in an e-mail to ARF. “It would have been more relevant to document the relative content of oligomeric Aβ molecules (e.g., dimers, trimers, Aβ*56, and annular protofibrils) present in all source material used.” (See comment below.) Lesne and others discussed challenges of studying physiologically relevant Aβ oligomers in a Webinar last week (see ARF Webinar).

Marc Diamond of Washington University School of Medicine in St. Louis, Missouri, noted that it may be difficult to extrapolate the findings to AD given the “rather peculiar system—microinjection of aggregates into mice that are ‘primed’ to form aggregates by virtue of overexpressing Aβ.”

For their part, Jucker said his team is forging ahead with studies in AD, pre-AD, and young patients to look for soluble Aβ seeds in body fluids, primarily cerebrospinal fluid.—Esther Landhuis


  1. This new study from Mathias Jucker's laboratory follows the steps of their previous work (Eisele et al., 2010) suggesting that Aβ possesses prion-like properties. Here, they refined their approach by showing that, not only did extracts from transgenic mouse brain induce amyloidosis following injection in younger animals, but also that both soluble and insoluble material (differentiated by a 100,000 x g ultracentrifugation step) derived from those extracts can reproduce this effect. There are qualitative and quantitative differences in the amyloidosis triggered by the soluble or the insoluble protein fraction. The authors report that despite constituting less than 1 percent of the total Aβ present in the extracts, the soluble fraction is capable of inducing amyloidosis. Based on proteinase K resistance assays, the authors conclude that multiple species/forms of Aβ may be necessary for inducing this effect.

    Even though this result is interesting and the experiments were carefully executed, several questions readily come to mind. The biochemical characterization of the soluble and insoluble fractions compared to the initial transgenic extract is quite modest, as only monomeric Aβ levels are reported. In my opinion, it would have been more relevant to document the relative content of oligomeric Aβ molecules (dimers, trimers, Aβ*56, and annular protofibrils) present in all source material used, especially since the potential involvement of these species is suggested by the authors in the discussion. For instance, multiple Aβ antibodies could have been used to further characterize the source material (by Western blot or ELISA). Without such analyses, it is difficult to extrapolate on the nature of the assemblies responsible for the induced amyloidosis. The last presented experiment using various durations of sonication might indicate that the "soluble" molecules at play are bound to plaques. If it is the case, one would expect to see increased Aβ dimers in the fraction most sonicated, as dimers were previously shown to bind to plaques (Shankar et al., 2008). Finally, it would have been intriguing to compare the soluble fraction of the transgenic extract containing 1 percent of total Aβ with an injectate made of the insoluble fraction containing that same 1 percent of total Aβ. Doing so would allow for a better appreciation of the relative importance of the nature (oligomeric vs. fibrillar) of the Aβ species involved in these effects.


    . Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science. 2010 Nov 12;330(6006):980-2. PubMed.

    . Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008 Aug;14(8):837-42. PubMed.

  2. This well-designed study is an extension of the previous outstanding studies published by Jucker's group on amyloid induction in vivo. In my opinion, it represents a significant step, fortunately, in the right direction. It clearly demonstrates that soluble Aβ assemblies are potent amyloid-inducing factors. More importantly, it demonstrates that the most effective seeds are also the most conformationally dynamic and likely to bind other proteins. This study makes clever use of many well-established protocols, such as fractionation, sonication, and proteinase K digestion, to pinpoint the most effective seed, which turned out to be mainly soluble. Evolution in the amyloid field continues, and I expect that in the near future the same scenario will be demonstrated for other proteins such as synuclein and tau. The only piece of data I wish that the authors had included is information about the hydrophobicity of the different fractions and their ability to bind dyes such as thioflavin T, Congo red, and 8-anilino-1-naphthalene sulfonate (ANS).

    View all comments by Rakez Kayed

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News Citations

  1. Double Paper Alert—A Function for BACE, a Basis for Amyloid
  2. Peripheral Aβ Seeds CAA and Parenchymal Amyloidosis
  3. Research Brief: α-synuclein Spoils the Neural Neighborhood
  4. Double Down: TDP-43 Fragments Bust Cells on Second Hit

Webinar Citations

  1. Seeded Aggregation and Transmissible Proteopathy—Creepy Stuff Not Just for Prions Anymore?
  2. Clearing the Fog Around Aβ Oligomers

Paper Citations

  1. . Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006 Sep 22;313(5794):1781-4. PubMed.
  2. . Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice. J Neurosci. 2000 May 15;20(10):3606-11. PubMed.
  3. . Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science. 2010 Nov 12;330(6006):980-2. PubMed.
  4. . The public health impact of prion diseases. Annu Rev Public Health. 2005;26:191-212. PubMed.
  5. . Evidence for the experimental transmission of cerebral beta-amyloidosis to primates. Int J Exp Pathol. 1993 Oct;74(5):441-54. PubMed.
  6. . Very long term studies of the seeding of beta-amyloidosis in primates. J Neural Transm. 2006 Sep;113(9):1243-51. PubMed.
  7. . Development of transgenic rats producing human beta-amyloid precursor protein as a model for Alzheimer's disease: transgene and endogenous APP genes are regulated tissue-specifically. BMC Neurosci. 2008;9:28. PubMed.
  8. . Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13010-5. PubMed.
  9. . α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011 Feb 1;121(2):715-25. PubMed.
  10. . Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat. Neurobiol Dis. 2011 Sep;43(3):552-7. PubMed.
  11. . Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol. 2009 Feb;11(2):219-25. PubMed.
  12. . Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis. PLoS One. 2010;5(5):e10627. PubMed.
  13. . Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3548-53. PubMed.
  14. . A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions. J Biol Chem. 2011 May 27;286(21):18664-72. PubMed.

Other Citations

  1. APP23 transgenic mice

External Citations

  1. HuAPPwt
  2. CBS News
  3. Fox News
  4. “accepted article”

Further Reading


  1. . Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice. J Neurosci. 2000 May 15;20(10):3606-11. PubMed.
  2. . Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science. 2010 Nov 12;330(6006):980-2. PubMed.
  3. . Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006 Sep 22;313(5794):1781-4. PubMed.

Primary Papers

  1. . De novo induction of amyloid-β deposition in vivo. Mol Psychiatry. 2011 Oct 4; PubMed.
  2. . Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition. J Neurosci. 2011 Oct 12;31(41):14488-95. PubMed.
  3. . Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol. 2011 Oct;70(4):532-40. PubMed.