Quaternary Structure of a Mature Amyloid Fibril from Alzheimer’s Aβ(1-40) Peptide

Sachse, Carsten; Xu, Chen; Wieligmann, Karin; Diekmann, Stephan; Grigorieff, Nikolaus; Fändrich, Marcus

doi:10.1016/j.jmb.2006.07.011

Cited by 68 publications

(86 citation statements)

References 35 publications

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“…The fibril was assumed to have a left-handed twist based on the AFM images (Fig. 1B), consistent with the reported handedness for other amyloid fibrils (18)(19)(20).…”

Section: A␤1-42 Fibrilssupporting

confidence: 76%

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Interprotofilament interactions between Alzheimer's Aβ _1–42 peptides in amyloid fibrils revealed by cryoEM

Zhang

Khant

et al. 2009

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

149

145

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Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of amyloid plaques in the brain. This amyloid primarily contains amyloid-␤ (A␤), a 39-to 43-aa peptide derived from the proteolytic cleavage of the endogenous amyloid precursor protein. The 42-residue-length A␤ peptide (A␤1-42), the most abundant A␤ peptide found in plaques, has a much greater propensity to self-aggregate into fibrils than the other peptides and is believed to be more pathogenic. Synthetic human A␤ 1-42 peptides self-aggregate into stable but poorly-ordered helical filaments. We determined their structure to Ϸ10-Å resolution by using cryoEM and the iterative real-space reconstruction method. This structure reveals 2 protofilaments winding around a hollow core. Previous hairpin-like NMR models for A␤17-42 fit well in the cryoEM density map and reveal that the juxtaposed protofilaments are joined via the N terminus of the peptide from 1 protofilament connecting to the loop region of the peptide in the opposite protofilament. This model of mature A␤ 1-42 fibrils is markedly different from previous cryoEM models of A␤1-40 fibrils. In our model, the C terminus of A␤ forms the inside wall of the hollow core, which is supported by partial proteolysis analysis.Alzheimer's disease ͉ iterative real-space reconstruction ͉ protein misfolding ͉ neurodegenerative disease ͉ amyloid plaques T he deposition and accumulation of amyloid is a characteristic pathology for Ͼ20 different human diseases. These diseases develop with the misfolding and aggregation of normally-soluble peptides resulting in self-aggregation and accumulation of large insoluble fibrils. One of the most common forms of dementia, Alzheimer's disease, shows typical deposition of amyloid in the form of plaques in the extracellular spaces of the brain. The principal component of these plaques is the A␤ peptide, a 39-to 43-aa cleavage product of the amyloid precursor protein. The most abundant A␤ peptide found in plaques is the 42-residue A␤ 1-42 , which has a remarkable propensity to self-aggregate at high concentrations. Indeed, compared with A␤ 1-40 , A␤ 1-42 demonstrates much more rapid fibril formation in vitro (1-3). In addition, recent studies in animal models demonstrate that A␤ 1-42 is exclusively required for the formation of plaques. In these mice, overexpression of A␤ 1-42 alone resulted in the development of plaque pathology, whereas A␤ 1-40 overexpression did not (4). Therefore, studying differences between A␤ 1-40 and A␤ and their aggregation products may be important in understanding pathological processes involved in fibril and plaque formation.Because of their highly insoluble but noncrystalline nature, structural determination of amyloid fibrils is refractory to traditional methods such as X-ray crystallography and solution NMR spectroscopy. Early X-ray fiber diffraction experiments revealed a generic cross-␤ structure for nearly all amyloid fibrils, in which in-register ␤-strands run approximately perpendicular to the fibril axis and the ␤-sh...

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“…The fibril was assumed to have a left-handed twist based on the AFM images (Fig. 1B), consistent with the reported handedness for other amyloid fibrils (18)(19)(20).…”

Section: A␤1-42 Fibrilssupporting

confidence: 76%

“…In comparing our cryoEM map of A␤ 1-42 fibril with previous cryoEM maps of A␤ fibril (20,30), there are some similarities but many striking differences. Both structures show that mature fibrils are assemblies of pairs of protofilaments.…”

Section: Discussionmentioning

confidence: 67%

Interprotofilament interactions between Alzheimer's Aβ _1–42 peptides in amyloid fibrils revealed by cryoEM

Zhang

Khant

et al. 2009

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

149

145

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“…1a) and current structural data on A␤(1-40) fibrils. The three complementarity determining regions that are responsible for the specificity of the VHH-domain span, in B10 homology model, a distance of 31 Å. X-ray diffraction measures, for A␤(1-40) amyloid fibrils, a peptide repeat of 4.76 Å (23). Hence, one molecule of B10 covers approximately seven molecules of A␤ .…”

Section: Resultsmentioning

confidence: 99%

Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Aβ protofibrils

Habicht

Haupt

Friedrich

et al. 2007

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

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205

242

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The formation of amyloid fibrils is a common biochemical characteristic that occurs in Alzheimer's disease and several other amyloidoses. The unifying structural feature of amyloid fibrils is their specific type of ␤-sheet conformation that differentiates these fibrils from the products of normal protein folding reactions. Here we describe the generation of an antibody domain, termed B10, that recognizes an amyloid-specific and conformationally defined epitope. This antibody domain was selected by phage-display from a recombinant library of camelid antibody domains. Surface plasmon resonance, immunoblots, and immunohistochemistry show that this antibody domain distinguishes A␤ amyloid fibrils from disaggregated A␤ peptide as well as from specific A␤ oligomers. The antibody domain possesses functional activity in preventing the formation of mature amyloid fibrils by stabilizing A␤ protofibrils. These data suggest possible applications of B10 in the detection of amyloid fibrils or in the modulation of their formation.neurodegeneration ͉ prion ͉ protein folding

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“…Fibril structures of Aβ 1−42 peptides Within this direct nucleation route, monomeric Aβ 1−42 peptides first undergo structural conversion from the α-state into β-state, and spontaneously stack along one direction to construct a nucleus of a protofilament, or fibrils with more than one protofilaments (typically this number lies between 2 to 6) [40][41][42][43][44] . These fibrils have a twisted linear structure along the fibril axis, making a complete pitch every 33 β-mers [45][46][47] .…”

Section: Nucleated Polymerization Modelmentioning

confidence: 99%

Mechanisms and rates of nucleation of amyloid fibrils

Lee

Terentjev

2017

The Journal of Chemical Physics

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The classical nucleation theory finds the rate of nucleation proportional to the monomer concentration raised to the power, which is the 'critical nucleaus size', n c . The implicit assumption, that amyloids nucleate in the same way, has been recently challenged by an alternative two-step mechanism, when the soluble monomers first form a metastable aggregate (micelle), and then undergo conversion into the conformation rich in β-strands that are able to form a stable growing nucleus for the protofilament. Here we put together the elements of extensive knowledge about aggregation and nucleation kinetics, using a specific case of Aβ 1−42 amyloidogenic peptide for illustration, to find theoretical expressions for the effective rate of amyloid nucleation. We find that at low monomer concentration in solution, and also at low interaction energy between two peptide conformations in the micelle, the nucleation occurs via the classical route. At higher monomer concentration, and a range of other interaction parameters between peptides, the two-step 'aggregation-conversion' mechanism of nucleation takes over. In this regime, the effective rate of the process can be interpreted as a power of monomer concentration in a certain range of parameters, however, the exponent is determined by a complicated interplay of interaction parameters and is not related to the minimum size of the growing nucleus (which we find to be ∼ 7-8 for Aβ 1−42 ).

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Quaternary Structure of a Mature Amyloid Fibril from Alzheimer’s Aβ(1-40) Peptide

Cited by 68 publications

References 35 publications

Interprotofilament interactions between Alzheimer's Aβ _1–42 peptides in amyloid fibrils revealed by cryoEM

Interprotofilament interactions between Alzheimer's Aβ _1–42 peptides in amyloid fibrils revealed by cryoEM

Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Aβ protofibrils

Mechanisms and rates of nucleation of amyloid fibrils

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Quaternary Structure of a Mature Amyloid Fibril from Alzheimer’s Aβ(1-40) Peptide

Cited by 68 publications

References 35 publications

Interprotofilament interactions between Alzheimer's Aβ 1–42 peptides in amyloid fibrils revealed by cryoEM

Interprotofilament interactions between Alzheimer's Aβ 1–42 peptides in amyloid fibrils revealed by cryoEM

Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Aβ protofibrils

Mechanisms and rates of nucleation of amyloid fibrils

Contact Info

Product

Resources

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Interprotofilament interactions between Alzheimer's Aβ _1–42 peptides in amyloid fibrils revealed by cryoEM

Interprotofilament interactions between Alzheimer's Aβ _1–42 peptides in amyloid fibrils revealed by cryoEM