All plaque cores may look similar under a brightfield microscope, but in the light of luminescent conjugated oligothiophenes, structural idiosyncrasies emerge. Researchers led by Mathias Jucker at the German Center for Neurodegenerative Diseases in Tübingen used this new class of dye to unveil the diverse structural conformations of Aβ fibrils. Though the fluorescent signatures of plaques varied, “clouds” of similar variants emerged among people with the same familial AD mutations or AD subtypes. The findings suggest that structural variations in Aβ fibrils underlie clinical manifestations of the disease.

  • A new class of fluorescent amyloid dye reveals a myriad of Aβ fibril structures.
  • Structural variants of different subtypes of AD segregated into “clouds” of spectral signatures.
  • Familial, sporadic, and atypical forms of AD have unique signatures.

A striking amount of heterogeneity exists in the structure of Aβ fibrils. Some fibrils, or strains, of Aβ propagate their unique shape when used to seed synthetic fibrils, or to inoculate AD mouse models (Oct 2011 newsSep 2013 news). Strains may differ among people as well, with unique fibrils linked to rapid- versus slow-progressing AD (Cohen et al., 2015Jan 2017 news). In one striking example of structural uniqueness, Aβ fibrils from one person with sporadic AD failed to bind PiB, but postmortem examination revealed the person’s brain was chock-full of plaques (Rosen et al., 2010). 

Is there some rhyme or reason behind this structural chaos? First author Jay Rasmussen and colleagues asked whether fibrils from different subtypes of AD shared common structures. The researchers turned to the luminescent conjugated oligothiophenes (LCOs) because their fluorescence depends on the type of repetitive cross-β-sheet structure they bind. Using the ratio of emission spectra from two different LCOs to define the “spectral signature” of Aβ fibrils, the researchers compared Aβ in plaques from postmortem tissue derived from 13 familial AD mutation carriers, 21 people with typical sporadic AD, and six people with sporadic posterior cortical atrophy (PCA-AD). The researchers determined the signatures of 40 to 60 plaques in each of the frontal, temporal, and occipital lobes in each person. Jucker presented the majority of the findings at AAIC last July (Aug 2017 conference news). 

In a nutshell, the researchers found commonalities in Aβ fibril structures among some, but not all, AD subgroups. The researchers likened the distribution of structural variations to clouds (see image below). For each plaque, the researchers plotted the fluorescence intensity at 502nm and 588nm, which represent the emission peaks of each of the two dyes used. The resulting spectral signatures were highly variable. Some coalesced into discernable blobs depending on AD subtype. Those from carriers of APP V717I or PSEN1 A431E mutations were most distinctive, forming tighter groupings that overlapped with those from other AD subtypes. Importantly, none of these mutations lie in the Aβ peptide, so their structural variations were not rooted in a sequence change. In contrast, signatures from plaques in people with sporadic AD were more scattered. PCA-AD plaques also varied, but differently from typical sporadic AD plaques. Interestingly, the structural variants of fibrils from the sporadic AD patients that failed to bind PiB aligned more closely with those from familial AD patients than those from others with sporadic disease. Though structural variability existed within each person as well, the average spectral signature of plaques in each region of the brain was similar. 

Plaque Patterns.

Fluorescence of LCO dyes at 502nm and 588nm suggests unique structures for each plaque, represented here by colored symbols. Signatures for each AD subgroup (see legend) were different, yet overlapped. [Courtesy of Rasmussen et al., PNAS 2017.]

The structural characteristics largely endured after the researchers injected the postmortem plaque material in each AD subgroup into APP23 mice and analyzed the brains six months later. The distribution of fluorescence spectra emitted from plaques in mice partially aligned with what had been observed in humans. 

Jucker told Alzforum that he does not know the biological basis for the Aβ fibril structures in the AD subtypes. Something about the unique brain environment might ultimately affect Aβ conformation, he proposed. Whether those conformations then influence the clinical phenotype of the disease remains to be seen, he added. Jucker also pointed out that the current study only examined postmortem samples from end-stage AD patients, and studies in people who died in earlier stages of the disease would be necessary to determine whether conformational differences exist from prodromal stages, and if they change as disease worsens. Researchers are also using LCOs to analyze the structure of Aβ in both CSF and blood from living patients, Jucker said.

“This is exciting and creative work,” commented David Brody from Washington University in St. Louis. “Like many advances, the new methods offer an opportunity to ask several new questions: Do plaques from non-demented controls (a.k.a. preclinical AD) have different dye-binding spectral signatures to plaques from AD patients? This could shed light on the characteristics most relevant for dementia.” Brody also wondered how the spectral signatures of plaques would relate to the degree of nearby synapse loss, and whether soluble oligomers might also have distinctive dye-binding properties that correlate with toxicity.—Jessica Shugart 


  1. I read with interest the intriguing finding of "distinct clouds of conformational variants" of amyloid, as reported by Rasmussen et al. This work adds to the concept that there are distinct strains of amyloid conformations that may be responsible for varying disease phenotypes in neurodegenerative disorders. The biological basis of these unique fibril structures may involve the microbiota. My coworkers and I have proposed that distinctive fibril structures of Aβ and related molecules may be caused by cross-seeding with amyloids produced by bacteria and fungi residing in the mouth, nose, and intestines (Friedland, 2015; Chen et al., 2016). Our microbiota are known to include many organisms that produce functional amyloid proteins, and cross-seeding of amyloid misfolding has been documented. The microbiota constitute our largest environmental exposure, and their potential role in AD and related disorders is worth consideration. 


    . Mechanisms of molecular mimicry involving the microbiota in neurodegeneration. J Alzheimers Dis. 2015;45(2):349-62. PubMed.

    . Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans. Sci Rep. 2016 Oct 6;6:34477. PubMed.

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News Citations

  1. Seeds of Destruction—Prion-like Transmission of Sporadic AD?
  2. Does Aβ Come In Strains? Glimpse Into Human Brain Suggests Yes
  3. Do Palettes of Aβ Fibril Strains Differ Among Alzheimer’s Subtypes?
  4. Monomeric Seeds and Oligomeric Clouds—Proteopathy News from AAIC

Paper Citations

  1. . Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β. Brain. 2015 Apr;138(Pt 4):1009-22. Epub 2015 Feb 15 PubMed.
  2. . Deficient high-affinity binding of Pittsburgh compound B in a case of Alzheimer's disease. Acta Neuropathol. 2010 Feb;119(2):221-33. PubMed.

Further Reading


  1. . Aβ seeds and prions: How close the fit?. Prion. 2017 Jul 4;11(4):215-225. Epub 2017 Jun 28 PubMed.

Primary Papers

  1. . Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease. Proc Natl Acad Sci U S A. 2017 Dec 5;114(49):13018-13023. Epub 2017 Nov 20 PubMed.