. Aβ seeds resist inactivation by formaldehyde. Acta Neuropathol. 2014 Oct;128(4):477-84. Epub 2014 Sep 6 PubMed.


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  1. In support of current thinking on Aβ species relevant to Alzheimer’s disease etiology, the recent article in Brain by Fritschi et al. extends previous studies by this group, led by Mathias Jucker.

    Using pre-plaque APP23 Tg mice, brain amyloid deposits were seeded in accelerated fashion using 100K x g, PBS-soluble supernatants either from plaque-containing APP23 Tg brain extracts (Langer  et al., 2011) or, in the recent article, from human AD brain extracts prepared in similar fashion. As little as 1 femtogram Aβ species from a 1000-fold diluted AD brain PBS extract represented an EC50 of sorts, triggering amyloid deposition after eight months in half the animals injected. In contrast, CSF from 14 individuals (including both AD and non-AD) injected into pre-plaque APP23 Tg brain either neat, or following concentration by 15-fold, did not induce plaque but harbored some degree of seeds able to trigger in vitro amyloid aggregate formation detected using super-resolution fluorescence microscopy. 

    Some questions arise from this interesting study, including whether normal human brain extract would contain plaque-inducing amyloid seeds. Previous reports of oligomers in normal human brain that could potentially act as seeds support such an experiment brain (Tomic  et al. 2009Lesne  et al., 2013Savage  et al., 2014). If control extracts containing oligomers don’t accelerate plaque in the APP23 Tg brains, or do so with reduced potency, this would suggest inherent difference in their nature. Extracts from pre-plaque APP23 Tg mice, extracts of aged APP23 Tg brain previously cleared of Aβ by immunoprecipitation, as well as extracts treated with proteinase K failed to accelerate plaque (Meyer-Luehmann  et al., 2006Langer  et al, 2011) and support the notions that 1) Aβ protein is involved and 2) some aspect of brain aging confers additional toxic elements to Aβ (e.g. N-terminal truncation).

    A second question is why CSF oligomers from AD patients did not confer a similar seeding effect despite overall higher levels of total Aβ compared with the most concentrated brain extract. Two recently published Aβ oligomer ELISAs (Hölttä  et al., 2013; Savage  et al., 2014) detected a range of Aβ oligomer levels in both AD and age-matched control CSF, but these concentrations were approximately 130-fold lower compared with oligomer levels present in PBS brain extracts (Savage  et al., 2014). Also, CSF in Fritschi et al. was collected into polypropylene tubes, which bind Aβ species, especially those ending in residue 42 (Lewczuk et al., 2006Pica-Mendez et al., 2010; Perret-Liaudet et al., 2012). This could have reduced seeding species below the threshold for plaque-inducing activity. Also, Langer  et al., found that sonicating APP23 Tg extracts increased the area of induced plaque compared with less or no sonication (also a bit of sonication in standard extraction method); perhaps sonicating CSF a bit would reveal greater seeding ability. Finally, CSF Aβ species were found to lack N-terminally truncated forms (consistent with Portelius  et al., 2007); this may be a key difference in ability to seed plaque as N-terminally truncated species are more amyloidogenic.

    Studying amyloid seeds following size fractionation on SEC and other analytical methods could further guide understanding of the aggregation drivers of this and potentially other insoluble proteins implicated in neurodegenerative diseases.


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    View all comments by Mary Savage
  2. This is another excellent study from the Jucker group, focusing on the seeding and transmission of Amyloid-β deposition in animal models of Alzheimer's disease. The article is very complete, well done, and clearly shows that CSF from AD patients or old AD transgenic mice does not carry seeding-competent Aβ aggregates capable of inducing pathogenesis in vivo. Despite the negative results in vivo, they show, in agreement with previous publications, that CSF does carry aggregates that are capable of seeding Aβ aggregation in vitro. This apparent contradictory result is not so surprising considering the example of prion diseases, in which it is common to find prion aggregates detectable in vitro in biological fluids such as blood or urine, which are not able to induce disease in animals. The reason is either that the quantity of these aggregates in the fluids is too low to sustain induction of pathogenesis in vivo or that, as suggested by the authors, the structure of the aggregates circulating in fluids is more labile than in the brain, and they get cleared when administered in vivo.

    View all comments by Claudio Soto

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  1. Bad Seeds—Potent Aβ Peptides Instigate Plaques, Won’t Be Fixed