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Aβ43 is neurotoxic and primes aggregation of Aβ40 in vivo.

Burnouf S, Gorsky MK, Dols J, Grönke S, Partridge L - Acta Neuropathol. (2015)

Bottom Line: However, whether Aβ43 is toxic in vivo is currently unclear.In addition, we demonstrate that Aβ43 species are able to trigger the aggregation of the typically soluble and non-toxic Aβ40, leading to synergistic toxic effects on fly lifespan and climbing ability, further suggesting that Aβ43 peptides could act as a nucleating factor in AD brains.Altogether, our study demonstrates high pathogenicity of Aβ43 species in vivo and supports the idea that Aβ43 contributes to the pathological events leading to neurodegeneration in AD.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931, Cologne, Germany.

ABSTRACT
The involvement of Amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD) is well established. However, it is becoming clear that the amyloid load in AD brains consists of a heterogeneous mixture of Aβ peptides, implying that a thorough understanding of their respective role and toxicity is crucial for the development of efficient treatments. Besides the well-studied Aβ40 and Aβ42 species, recent data have raised the possibility that Aβ43 peptides might be instrumental in AD pathogenesis, because they are frequently observed in both dense and diffuse amyloid plaques from human AD brains and are highly amyloidogenic in vitro. However, whether Aβ43 is toxic in vivo is currently unclear. Using Drosophila transgenic models of amyloid pathology, we show that Aβ43 peptides are mainly insoluble and highly toxic in vivo, leading to the progressive loss of photoreceptor neurons, altered locomotion and decreased lifespan when expressed in the adult fly nervous system. In addition, we demonstrate that Aβ43 species are able to trigger the aggregation of the typically soluble and non-toxic Aβ40, leading to synergistic toxic effects on fly lifespan and climbing ability, further suggesting that Aβ43 peptides could act as a nucleating factor in AD brains. Altogether, our study demonstrates high pathogenicity of Aβ43 species in vivo and supports the idea that Aβ43 contributes to the pathological events leading to neurodegeneration in AD.

No MeSH data available.


Related in: MedlinePlus

Aβ43 triggered toxicity from Aβ40. Climbing performance (a) and survival curves (b) of fly lines expressing 1×Aβ40 (grey), 1×Aβ43 (green) or the combination of Aβ40+Aβ40 (blue) or Aβ40+Aβ43 (navy blue) in adult neurons using the elavGS driver. The inset shows the percentage of median lifespan reduction vs. non-induced control. ****p < 0.0001 vs. non-induced controls, two-way ANOVA. c qRT-PCR analysis of Aβ mRNA levels from head extracts of Aβ40+Aβ40 and Aβ40+Aβ43 lines (p > 0.05, Student’s t test)
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Fig6: Aβ43 triggered toxicity from Aβ40. Climbing performance (a) and survival curves (b) of fly lines expressing 1×Aβ40 (grey), 1×Aβ43 (green) or the combination of Aβ40+Aβ40 (blue) or Aβ40+Aβ43 (navy blue) in adult neurons using the elavGS driver. The inset shows the percentage of median lifespan reduction vs. non-induced control. ****p < 0.0001 vs. non-induced controls, two-way ANOVA. c qRT-PCR analysis of Aβ mRNA levels from head extracts of Aβ40+Aβ40 and Aβ40+Aβ43 lines (p > 0.05, Student’s t test)

Mentions: Noteworthy, next to its propensity to self-aggregate, Aβ43 has also been implicated in the seeding of other Aβ peptides based on in vitro data and co-localisation studies [29, 38], an effect potentially enhancing overall Aβ toxicity. To test whether this process occurred in vivo, we used our Drosophila transgenic lines to stoichiometrically induce Aβ43 expression together with that of the non-toxic Aβ40 and to evaluate whether this combination would trigger toxicity. To that end, we titrated down Aβ43 levels by halving transgene copy number from two copies to one, leading to no detectable toxicity in terms of climbing ability (1×Aβ43, Fig. 6a) or median lifespan (1×Aβ43, Fig. 6b), similar to the effects obtained following halved expression of Aβ40 (1×Aβ40, Fig. 6a, b). While combining Aβ40 with Aβ40 itself (Aβ40+Aβ40) did not lead to any phenotypic changes as compared to Aβ40 alone (p > 0.05, Fig. 6a, b), we observed that the combination of low levels of both Aβ40 and Aβ43 induced synergistic toxic effects both on climbing ability (****p < 0.0001 vs. non-induced-Aβ40+Aβ43 controls and vs. all other induced lines at day 25, two-way ANOVA, Fig. 6a) and survival (median lifespan: −15.7 % of the non-induced controls, p < 0.0001, log-rank test, Fig. 6b), suggesting that Aβ43 was able to trigger toxicity from Aβ40 peptides in vivo, despite the ordinarily harmless nature of the latter. We used the same experimental setup to co-express Aβ40 with Aβ42 (supplementary Fig. 4), which led to drastic detrimental effects, both on climbing ability (****p < 0.0001 vs. non-induced-Aβ40+Aβ42 controls and vs. all other induced lines at day 18, two-way ANOVA, supplementary Fig. 4a) and survival (median lifespan: −46.7 % of the non-induced controls, p < 0.0001, log-rank test, supplementary Fig. 4b). Even though both Aβ40+Aβ42 and Aβ40+Aβ43 combinations led to significant synergistic toxic effects in the fly nervous system, it appeared that the former triggered stronger toxicity. We therefore investigated whether Aβ43 could modulate Aβ42 toxicity by comparing the effect of Aβ42+Aβ43 with that of Aβ42+Aβ42 on climbing ability and survival of flies (supplementary Fig. 5). We could observe a rather modest but yet significant reduction of toxicity in the combined Aβ42+Aβ43 line both in terms of climbing (**p < 0.01, induced-Aβ42+Aβ43 vs. induced-Aβ42+Aβ42, two-way ANOVA, supplementary Fig. 5a) and survival (p < 0.0001, induced-Aβ42+Aβ43 vs. induced-Aβ42+Aβ42, log-rank test, supplementary Fig. 5b). Importantly, we evaluated Aβ transcript levels among the lines in all three experiments and observed that they were comparable (p > 0.05, Aβ40+Aβ40 vs. Aβ40+Aβ43, Fig. 6c, Aβ40+Aβ40 vs. Aβ40+Aβ42, supplementary Fig. 4c, and Aβ42+Aβ42 vs. Aβ42+Aβ43, supplementary Fig. 5c, using Student’s t test), implying that the toxic interaction we observed between the Aβ isoforms was taking place at the protein level.Fig. 6


Aβ43 is neurotoxic and primes aggregation of Aβ40 in vivo.

Burnouf S, Gorsky MK, Dols J, Grönke S, Partridge L - Acta Neuropathol. (2015)

Aβ43 triggered toxicity from Aβ40. Climbing performance (a) and survival curves (b) of fly lines expressing 1×Aβ40 (grey), 1×Aβ43 (green) or the combination of Aβ40+Aβ40 (blue) or Aβ40+Aβ43 (navy blue) in adult neurons using the elavGS driver. The inset shows the percentage of median lifespan reduction vs. non-induced control. ****p < 0.0001 vs. non-induced controls, two-way ANOVA. c qRT-PCR analysis of Aβ mRNA levels from head extracts of Aβ40+Aβ40 and Aβ40+Aβ43 lines (p > 0.05, Student’s t test)
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Related In: Results  -  Collection

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Fig6: Aβ43 triggered toxicity from Aβ40. Climbing performance (a) and survival curves (b) of fly lines expressing 1×Aβ40 (grey), 1×Aβ43 (green) or the combination of Aβ40+Aβ40 (blue) or Aβ40+Aβ43 (navy blue) in adult neurons using the elavGS driver. The inset shows the percentage of median lifespan reduction vs. non-induced control. ****p < 0.0001 vs. non-induced controls, two-way ANOVA. c qRT-PCR analysis of Aβ mRNA levels from head extracts of Aβ40+Aβ40 and Aβ40+Aβ43 lines (p > 0.05, Student’s t test)
Mentions: Noteworthy, next to its propensity to self-aggregate, Aβ43 has also been implicated in the seeding of other Aβ peptides based on in vitro data and co-localisation studies [29, 38], an effect potentially enhancing overall Aβ toxicity. To test whether this process occurred in vivo, we used our Drosophila transgenic lines to stoichiometrically induce Aβ43 expression together with that of the non-toxic Aβ40 and to evaluate whether this combination would trigger toxicity. To that end, we titrated down Aβ43 levels by halving transgene copy number from two copies to one, leading to no detectable toxicity in terms of climbing ability (1×Aβ43, Fig. 6a) or median lifespan (1×Aβ43, Fig. 6b), similar to the effects obtained following halved expression of Aβ40 (1×Aβ40, Fig. 6a, b). While combining Aβ40 with Aβ40 itself (Aβ40+Aβ40) did not lead to any phenotypic changes as compared to Aβ40 alone (p > 0.05, Fig. 6a, b), we observed that the combination of low levels of both Aβ40 and Aβ43 induced synergistic toxic effects both on climbing ability (****p < 0.0001 vs. non-induced-Aβ40+Aβ43 controls and vs. all other induced lines at day 25, two-way ANOVA, Fig. 6a) and survival (median lifespan: −15.7 % of the non-induced controls, p < 0.0001, log-rank test, Fig. 6b), suggesting that Aβ43 was able to trigger toxicity from Aβ40 peptides in vivo, despite the ordinarily harmless nature of the latter. We used the same experimental setup to co-express Aβ40 with Aβ42 (supplementary Fig. 4), which led to drastic detrimental effects, both on climbing ability (****p < 0.0001 vs. non-induced-Aβ40+Aβ42 controls and vs. all other induced lines at day 18, two-way ANOVA, supplementary Fig. 4a) and survival (median lifespan: −46.7 % of the non-induced controls, p < 0.0001, log-rank test, supplementary Fig. 4b). Even though both Aβ40+Aβ42 and Aβ40+Aβ43 combinations led to significant synergistic toxic effects in the fly nervous system, it appeared that the former triggered stronger toxicity. We therefore investigated whether Aβ43 could modulate Aβ42 toxicity by comparing the effect of Aβ42+Aβ43 with that of Aβ42+Aβ42 on climbing ability and survival of flies (supplementary Fig. 5). We could observe a rather modest but yet significant reduction of toxicity in the combined Aβ42+Aβ43 line both in terms of climbing (**p < 0.01, induced-Aβ42+Aβ43 vs. induced-Aβ42+Aβ42, two-way ANOVA, supplementary Fig. 5a) and survival (p < 0.0001, induced-Aβ42+Aβ43 vs. induced-Aβ42+Aβ42, log-rank test, supplementary Fig. 5b). Importantly, we evaluated Aβ transcript levels among the lines in all three experiments and observed that they were comparable (p > 0.05, Aβ40+Aβ40 vs. Aβ40+Aβ43, Fig. 6c, Aβ40+Aβ40 vs. Aβ40+Aβ42, supplementary Fig. 4c, and Aβ42+Aβ42 vs. Aβ42+Aβ43, supplementary Fig. 5c, using Student’s t test), implying that the toxic interaction we observed between the Aβ isoforms was taking place at the protein level.Fig. 6

Bottom Line: However, whether Aβ43 is toxic in vivo is currently unclear.In addition, we demonstrate that Aβ43 species are able to trigger the aggregation of the typically soluble and non-toxic Aβ40, leading to synergistic toxic effects on fly lifespan and climbing ability, further suggesting that Aβ43 peptides could act as a nucleating factor in AD brains.Altogether, our study demonstrates high pathogenicity of Aβ43 species in vivo and supports the idea that Aβ43 contributes to the pathological events leading to neurodegeneration in AD.

View Article: PubMed Central - PubMed

Affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931, Cologne, Germany.

ABSTRACT
The involvement of Amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD) is well established. However, it is becoming clear that the amyloid load in AD brains consists of a heterogeneous mixture of Aβ peptides, implying that a thorough understanding of their respective role and toxicity is crucial for the development of efficient treatments. Besides the well-studied Aβ40 and Aβ42 species, recent data have raised the possibility that Aβ43 peptides might be instrumental in AD pathogenesis, because they are frequently observed in both dense and diffuse amyloid plaques from human AD brains and are highly amyloidogenic in vitro. However, whether Aβ43 is toxic in vivo is currently unclear. Using Drosophila transgenic models of amyloid pathology, we show that Aβ43 peptides are mainly insoluble and highly toxic in vivo, leading to the progressive loss of photoreceptor neurons, altered locomotion and decreased lifespan when expressed in the adult fly nervous system. In addition, we demonstrate that Aβ43 species are able to trigger the aggregation of the typically soluble and non-toxic Aβ40, leading to synergistic toxic effects on fly lifespan and climbing ability, further suggesting that Aβ43 peptides could act as a nucleating factor in AD brains. Altogether, our study demonstrates high pathogenicity of Aβ43 species in vivo and supports the idea that Aβ43 contributes to the pathological events leading to neurodegeneration in AD.

No MeSH data available.


Related in: MedlinePlus