Amyloid β-Protein Assembly and Alzheimer’s Disease: Dodecamers of Aβ42, but Not of Aβ40, Seed Fibril Formation

Economou, Nicholas J.; Giammona, Maxwell J.; Thanh, D.; Zheng, Xueyun; Teplow, David B.; Buratto, Steven K.; Bowers, Michael T.

doi:10.1021/jacs.5b11913

Cited by 122 publications

(145 citation statements)

References 39 publications

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“…Fibrils of both peptides have a typical amyloid morphology (~10 nm in width). These results confirm that both systems eventually form fibrils, as previously observed 46 indicating typical β -sheet structure. 47 …”

Section: Resultssupporting

confidence: 91%

1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose binds to the N-terminal metal binding region to inhibit amyloid β-protein oligomer and fibril formation

Almeida

Thanh

LaPointe

et al. 2017

International Journal of Mass Spectrometry

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The early oligomerization of amyloid β-protein (Aβ) is a crucial step in the etiology of Alzheimer’s disease (AD), in which soluble and highly neurotoxic oligomers are produced and accumulated inside neurons. In search of therapeutic solutions for AD treatment and prevention, potent inhibitors that remodel Aβ assembly and prevent neurotoxic oligomer formation offer a promising approach. In particular, several polyphenolic compounds have shown anti-aggregation properties and good efficacy on inhibiting oligomeric amyloid formation. 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose is a large polyphenol that has been shown to be effective at inhibiting aggregation of full-length Aβ1-40 and Aβ1-42, but has the opposite effect on the C-terminal fragment Aβ25-35. Here, we use a combination of ion mobility coupled to mass spectrometry (IMS-MS), transmission electron microscopy (TEM) and molecular dynamics (MD) simulations to elucidate the inhibitory effect of PGG on aggregation of full-length Aβ1-40 and Aβ1-42. We show that PGG interacts strongly with these two peptides, especially in their N-terminal metal binding regions, and suppresses the formation of Aβ1-40 tetramer and Aβ1-42 dodecamer. By exploring multiple facets of polyphenol-amyloid interactions, we provide a molecular basis for the opposing effects of PGG on full-length Aβ and its C-terminal fragments.

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Section: Resultssupporting

confidence: 91%

1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose binds to the N-terminal metal binding region to inhibit amyloid β-protein oligomer and fibril formation

Almeida

Thanh

LaPointe

et al. 2017

International Journal of Mass Spectrometry

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“…The story is very different for Aβ40 (65). In this instance no hexamers or dodecamers are detected by AFM at early times, only smaller oligomers.…”

Section: Case 1: Amyloid β-Protein and Alzheimer’s Disease (Ad)mentioning

confidence: 97%

“…In this regard we have recently published work in collaboration with Professor Steve Buratto at UCSB on the Aβ-peptide systems using ultra high resolution atomic force microscopy with the data summarized in Figure 4 (65). …”

Section: Case 1: Amyloid β-Protein and Alzheimer’s Disease (Ad)mentioning

confidence: 99%

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The Solution Assembly of Biological Molecules Using Ion Mobility Methods: From Amino Acids to Amyloid β-Protein

Bleiholder

Bowers

2017

Annual Rev. Anal. Chem.

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Ion mobility spectrometry-mass spectrometry (IMS-MS) methods are increasingly used to study noncovalent assemblies of peptides and proteins. This review focuses on the noncovalent self-assembly of amino acids and peptides, systems at the heart of the amyloid process that play a central role in a number of devastating diseases. Three different systems are discussed in detail: the 42-residue peptide amyloid-β42 implicated in the etiology of Alzheimer's disease, several amyloid-forming peptides with 6–11 residues, and the assembly of individual amino acids. We also discuss from a more fundamental perspective the processes that determine how quickly proteins and their assemblies denature when the analyte ion has been stripped of its solvent in an IMS-MS measurement and how to soften the measurement so that biologically meaningful data can be recorded.

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“…Applying native gel analyses of full-length tau and deletion constructs, the Bowers’ group demonstrated that the N-terminal region produced multiple bands, which was consistent with oligomerization [43]. High resolution atomic force microscopy was used to directly image populations of small oligomers and observe features that can be attributed to oligomers with different number of subunits [44]. By combining electron cryomicroscopy, 3D reconstruction, and integrative structural modeling methods, Matthias Schmidt and co-workers determined the molecular architecture of a fibril formed by Aβ(1–42).…”

Section: Resultsmentioning

confidence: 99%

Structural Characterization of Monomers and Oligomers of D-Amino Acid-Containing Peptides Using T-Wave Ion Mobility Mass Spectrometry

Pang

Jia

Chen

2016

J. Am. Soc. Mass Spectrom.

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The D-residues in D-amino acid containing peptides (DAACPs) are proven crucial to biological function of these peptides. Previous ion mobility mass spectrometry (IM-MS) studies revealing oligomerization patterns of amyloid cascade demonstrated conversion from native soluble unstructured assembly to fibril β-sheet oligomers, which has been implicated in amyloid diseases, such as Alzheimer’s disease and type 2 diabetes. Although neuropeptides are typically present at very low concentrations in circulation, their local concentrations could be much higher in large dense core vesicles, forming dimers or oligomers. We studied the oligomerization of the protonated peptides and metal adducts of achatin I and dermorphin peptide isomers with IM-MS. Our results suggested that dimerization, oligomerization and metal adduction augment the structural differences between D/L peptide isomers. Dimers and oligomers enhanced the structural differences between D/L peptide isomers in both aqueous and organic solvent system. Furthermore, some oligomer forms were only observed for either D- or L- isomers, indicating the importance of chiral center in oligomerization process. The oligomerization patterns of D/L isomers appear to be similar. Potassium adducts were detected to enlarge the structural differences between D- and L- isomers.

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Amyloid β-Protein Assembly and Alzheimer’s Disease: Dodecamers of Aβ42, but Not of Aβ40, Seed Fibril Formation

Cited by 122 publications

References 39 publications

1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose binds to the N-terminal metal binding region to inhibit amyloid β-protein oligomer and fibril formation

1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose binds to the N-terminal metal binding region to inhibit amyloid β-protein oligomer and fibril formation

The Solution Assembly of Biological Molecules Using Ion Mobility Methods: From Amino Acids to Amyloid β-Protein

Structural Characterization of Monomers and Oligomers of D-Amino Acid-Containing Peptides Using T-Wave Ion Mobility Mass Spectrometry

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