Structural Basis for Increased Toxicity of Pathological Aβ42:Aβ40 Ratios in Alzheimer Disease

Pauwels, Kris; Williams, Thomas L.; Morris, Kyle L.; Jonckheere, Wim; Vandersteen, Annelies; Kelly, Geoff; Schymkowitz, Joost; Rousseau, Frédéric; Pastore, Annalisa; Serpell, Louise C.; Broersen, Kerensa

doi:10.1074/jbc.m111.264473

Cited by 220 publications

(244 citation statements)

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“…In apparent contrast, previous in vitro studies have reported that assemblies of Ab protofibrils with different Ab40/42 ratios have similar molecular structures [27,28]. However, in vivo and within a cellular environment Ab aggregation is likely different [10].…”

Section: Transmission Of Ab Morphotypesmentioning

confidence: 73%

Seeded strain‐like transmission of β‐amyloid morphotypes in APP transgenic mice

et al. 2013

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The polymorphic b-amyloid lesions present in individuals with Alzheimer's disease are collectively known as cerebral b-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop b-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and Ab40/Ab42 peptide ratio. To determine the nature of such b-amyloid morphotypes, b-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally injected into the hippocampus of young APP23 or APPPS1 transgenic mice. APPPS1 brain extract injected into young APP23 mice induced b-amyloid deposition with the morphological, conformational, and Ab40/Ab42 ratio characteristics of b-amyloid deposits in aged APPPS1 mice, whereas APP23 brain extract injected into young APP23 mice induced b-amyloid deposits with the characteristics of b-amyloid deposits in aged APP23 mice. Injecting the two extracts into the APPPS1 host revealed a similar difference between the induced b-amyloid deposits, although less prominent, and the induced deposits were similar to the b-amyloid deposits found in aged APPPS1 hosts. These results indicate that the molecular composition and conformation of aggregated Ab in APP transgenic mice can be maintained by seeded conversion.

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Section: Transmission Of Ab Morphotypesmentioning

confidence: 73%

Seeded strain‐like transmission of β‐amyloid morphotypes in APP transgenic mice

et al. 2013

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“…By using this method, we successfully decoupled the aggregation from the HDX process. Importantly, we extracted kinetic information on the Aβ 42 aggregation at 25°C, indicating that the middle region of the Aβ 42 peptide (i.e., [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] was the "seeding" region in aggregation, followed by the C-terminus hydrophobic region (i.e., [36][37][38][39][40][41][42] and then the N-terminus hydrophilic region (i.e., [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Finally, we showed that this approach allowed us to examine directly the factors that affect the oligomerization of Aβ 42 .…”

Section: Resultsmentioning

confidence: 99%

“…Upon pulsed HDX of the preformed fibrils we observed both the peptides formed by pepsin digestion (i.e., [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and the undigested Aβ 42 . The peptides and the full Aβ 42 are similarly protected (89 ± 1% for the undigested Aβ 42 and 85 ± 1%, 84 ± 1%, and 91 ± 2% for 1-19, 20-35 and 36-42, respectively), consistent with the peptides' being proteolytic fragments from the amyloid fibrils.…”

Section: Application Of Finke-watzky Modeling and Statistical Evaluatmentioning

confidence: 99%

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Pulsed hydrogen–deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aβ) peptide aggregation

Zhang

Rempel

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

113

179

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Probing the conformational changes of amyloid beta (Aβ) peptide aggregation is challenging owing to the vast heterogeneity of the resulting soluble aggregates. To investigate the formation of these aggregates in solution, we designed an MS-based biophysical approach and applied it to the formation of soluble aggregates of the Aβ 42 peptide, the proposed causative agent in Alzheimer's disease. The approach incorporates pulsed hydrogen-deuterium exchange coupled with MS analysis. The combined approach provides evidence for a self-catalyzed aggregation with a lag phase, as observed previously by fluorescence methods. Unlike those approaches, pulsed hydrogen-deuterium exchange does not require modified Aβ 42 (e.g., labeling with a fluorophore). Furthermore, the approach reveals that the center region of Aβ 42 is first to aggregate, followed by the C and N termini. We also found that the lag phase in the aggregation of soluble species is affected by temperature and Cu 2+ ions. This MS approach has sufficient structural resolution to allow interrogation of Aβ aggregation in physiologically relevant environments. This platform should be generally useful for investigating the aggregation of other amyloid-forming proteins and neurotoxic soluble peptide aggregates.soluble Aβ oligomers | amyloid beta peptide | copper | electrospray ionization | Finke-Watsky mode P rotein aggregation is one of the immediate causes of Alzheimer's, Parkinson, and Huntington diseases, motivating biophysical studies of the responsible proteins. More than 20 small proteins undergo amyloidosis in humans. In Alzheimer's disease (AD), the aggregation of the 40-or 42-aa-long amyloid beta (Aβ) peptide, generally called Aβ 40 or Aβ 42 , respectively, is proposed to be involved in the onset of the disease (1, 2). Aβ 42 is more amyloidogenic and more neurotoxic than Aβ 40 . Although the amyloid-cascade hypothesis suggests that the Aβ-containing amyloid plaques are responsible for neurodegeneration (3-7), other studies suggest that soluble aggregates of Aβ 42 are more neurotoxic than the amyloid plaques (8-13).The amyloid plaques in AD-affected brains contain high levels of copper, zinc, and iron (14-20). Among these, Cu has drawn the most attention because the Aβ precursor protein is likely a Cuchaperone protein (21). Several studies of Cu 2+ -Aβ 40 interactions show that Cu 2+ can promote Aβ 40 aggregation (14,18,19).The structure of Aβ 42 and its aggregates, although studied extensively, remains of high interest. Studies of amyloid fibrils invoke X-ray crystallography (22-24), EM (19,25,26), and thioflavin T fluorescence (19, 27), revealing the polypeptide's global behavior, whereas NMR studies provide residue-level information for the fibrils (28-30). Nevertheless, we know little about soluble Aβ aggregates owing to their intrinsically high heterogeneity.MS should offer an opportunity for investigating soluble aggregates of Aβ 42 . Thus far, there are no MS-based, timedependent studies of the formation of soluble aggregates. Moreover, there are no ot...

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“…Although various Aβ fragments, such as 1-28, 25-35, and 34-42, have shown similar biochemical and biophysical properties to fulllength Aβ, 12-14 the establishment of structural models of fulllength Aβ has been desired because full-length Aβ is responsible for the pathogenesis of AD. [15][16][17][18] Here, we investigated the secondary structure of aggregated Aβ(1-40) and Aβ in an aqueous environment with VCD spectroscopy. VCD spectroscopy, where one measures the circular dichroism activity in the molecular vibration region, is a powerful tool for the discrimination of slight differences between secondary structures of peptides and proteins in aqueous environments.…”

Section: Introductionmentioning

confidence: 99%

Structural Discrimination between Aβ(1–40) and Aβ(1–42) Peptides in Films with Vibrational Circular Dichroism Spectroscopy

Morisaku

Yui

2017

ANAL. SCI.

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The secondary structure of full-length Aβ(1-40) and Aβ(1-42) peptides in films has been investigated with IR and vibrational circular dichroism (VCD) spectroscopy. From IR spectra, it is shown that the prepared films of Aβ(1-40) and Aβ(1-42) mainly comprise the β-sheet conformation that is characteristic of aggregated and fibrous Aβ. In the VCD spectra, the Aβ(1-42) film shows an intense and sharp band with left-handed optical activity at around 1625 cm -1 , while the Aβ(1-40) film shows a weak and broad band with right-handed activity at around 1630 cm -1 . The wavenumbers are characteristic of the β-sheet conformation. It has been clarified that the aggregated Aβ(1-42) adopts the β-sheet conformation with reverse optical activity compared with the aggregated Aβ(1-40). The left-handed optically active β-sheet of the aggregated Aβ(1-42) may contribute to the formation of protofibrils, which are a cause for the higher neurotoxicity of Aβ(1-42) fibrils than Aβ(1-40) fibrils.

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Structural Basis for Increased Toxicity of Pathological Aβ42:Aβ40 Ratios in Alzheimer Disease

Cited by 220 publications

References 43 publications

Seeded strain‐like transmission of β‐amyloid morphotypes in APP transgenic mice

Seeded strain‐like transmission of β‐amyloid morphotypes in APP transgenic mice

Pulsed hydrogen–deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aβ) peptide aggregation

Structural Discrimination between Aβ(1–40) and Aβ(1–42) Peptides in Films with Vibrational Circular Dichroism Spectroscopy

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