<i>In situ</i>
            atomic force microscopy study of Alzheimer’s β-amyloid peptide on different substrates: New insights into mechanism of β-sheet formation

Kowalewski, Tomasz; Holtzman, David M.

doi:10.1073/pnas.96.7.3688

Cited by 394 publications

(385 citation statements)

References 55 publications

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“…4B). This size is in good agreement with that of a protofilament (Ϸ45 ϫ 25 Å) in previous cryoEM images of 35Mox A␤ 1-42 fibrils (21) and with the protofilament dimensions deduced from AFM images (22)(23)(24). This large-density region is able to accommodate 2 ␤-sheets, fitting well with a recent hairpin-like NMR model for A␤ (21) (Protein Data Bank ID code 2BEG) (Fig.…”

Section: A␤1-42 Fibrilssupporting

confidence: 73%

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.

150

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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Section: A␤1-42 Fibrilssupporting

confidence: 73%

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.

150

145

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“…The aggregation mechanism of amyloid peptides and its relation to the pathological process by surface mediation can be expounded. Recently, many surfaces have been demonstrated to be able to mediate the amyloid fibril formation, including nanoparticles,9 polymeric films,10 charged mica,11 and graphite 12. For instance, on graphite, the lamella structure of assembled peptides with antiparallel β‐sheet secondary structure was revealed by scanning tunneling microscopy (STM), which is proposed to be closely related to the amyloid fibrillization 13…”

Section: Introductionmentioning

confidence: 99%

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

Liu

Zhang

et al. 2016

Advanced Science

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The differentiation of protein properties and biological functions arises from the variation in the primary and secondary structure. Specifically, in abnormal assemblies of protein, such as amyloid peptide, the secondary structure is closely correlated with the stable ensemble and the cytotoxicity. In this work, the early Aβ33‐42 aggregates forming the molecular monolayer at hydrophobic interface are investigated. The molecular monolayer of amyloid peptide Aβ33‐42 consisting of novel parallel β‐strand‐like structure is further revealed by means of a quantitative nanomechanical spectroscopy technique with force controlled in pico‐Newton range, combining with molecular dynamic simulation. The identified parallel β‐strand‐like structure of molecular monolayer is distinct from the antiparallel β‐strand structure of Aβ33‐42 amyloid fibril. This finding enriches the molecular structures of amyloid peptide aggregation, which could be closely related to the pathogenesis of amyloid disease.

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“…In addition to a series of factors (4-6) previously discovered to modulate peptide self-assembly, solid substrates have been found to drive this process directly acting as templates (7,8), controlling both assembly kinetics and morphology of amyloid peptide aggregates (8-11). These findings emphasize the importance of the substrate surface, whether it be a cellular membrane or an inorganic solid surface, on the assembly of various peptides, which is critical in many biological processes.…”

mentioning

confidence: 99%

Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface

Dai

Kang

Huynh

et al. 2013

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

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Surface-assisted self-assembly of amyloid-like peptides has received considerable interest in both amyloidosis research and nanotechnology in recent years. Despite extensive studies, some controlling factors, such as salts, are still not well understood, even though it is known that some salts can promote peptide selfassemblies through the so-called "salting-out" effect. However, they are usually noncontrollable, disordered, amorphous aggregates. Here, we show via a combined experimental and theoretical approach that a conserved consensus peptide NH 2 -VGGAVVAGV-CONH 2 (GAV-9) (from representative amyloidogenic proteins) can self-assemble into highly ordered, multilayered nanofilaments, with surprising all-upright conformations, under high-salt concentrations. Our atomic force microscopy images also demonstrate that the vertical stacking of multiple layers is highly controllable by tuning the ionic strength, such as from 0 mM (monolayer) to 100 mM (mainly double layer), and to 250 mM MgCl 2 (double, triple, quadruple, and quintuple layers). Our atomistic molecular dynamics simulations then reveal that these individual layers have very different internal nanostructures, with parallel β-sheets in the first monolayer but antiparallel β-sheets in the subsequent upper layers due to their different microenvironment. Further studies show that the growth of multilayered, all-upright nanostructures is a common phenomenon for GAV-9 at the mica/water interface, under a variety of salt types and a wide range of salt concentrations.amyloid peptide | atomic force microscopy | salt effect | self-assembly on mica A better understanding of the self-assembly of highly ordered peptide nanostructures is critical because it not only helps to uncover the pathogenesis of various neurodegenerative diseases (1) but provides an attractive "bottom-up" nanotechnology for de novo nanodevice design (2) and fabrication (3). In addition to a series of factors (4-6) previously discovered to modulate peptide self-assembly, solid substrates have been found to drive this process directly acting as templates (7,8), controlling both assembly kinetics and morphology of amyloid peptide aggregates (8-11). These findings emphasize the importance of the substrate surface, whether it be a cellular membrane or an inorganic solid surface, on the assembly of various peptides, which is critical in many biological processes. It has been shown recently that fibrous nanostructures form a fundamental framework ubiquitous in normal cellular metabolism, including cell division and signaling, as well as in over 27 different human amyloid diseases and 9 in animals (12).Due to the complexity of cellular membranes and associated physiological conditions (13,14), hydrophilic mica and hydrophobic highly oriented pyrolytic graphite (HOPG) are the two commonly used model substrates for the investigation of surface effects (10,11,15). For example, it was found that amyloid-β (Aβ) peptide formed oligomeric protofibrillar aggregates on mica but only 1D nanofilaments on HOPG (...

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In situ atomic force microscopy study of Alzheimer’s β-amyloid peptide on different substrates: New insights into mechanism of β-sheet formation

Cited by 394 publications

References 55 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

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface

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In situ atomic force microscopy study of Alzheimer’s β-amyloid peptide on different substrates: New insights into mechanism of β-sheet formation

Cited by 394 publications

References 55 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

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

Salts drive controllable multilayered upright assembly of amyloid-like peptides at mica/water interface

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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