The amyloid‐β peptide and its role in Alzheimer's disease

Clippingdale, Andrew B.; Wade, John D.; Barrow, Colin J.

doi:10.1002/psc.324

Cited by 86 publications

(56 citation statements)

References 208 publications

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“…[31] This aspect seems to be a general feature of the peptide not only in solution but even in the solid state. [32] By using an integrated approach of experimental and theoretical methods, we have in this work tried to follow and describe, with as much structural detail as possible, the conformational transitions of Ab-(1-42) when transferred from a very apolar to a fully polar medium.…”

Section: Discussionmentioning

confidence: 99%

The α‐to‐β Conformational Transition of Alzheimer's Aβ‐(1–42) Peptide in Aqueous Media is Reversible: A Step by Step Conformational Analysis Suggests the Location of β Conformation Seeding

et al. 2006

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Current views of the role of beta-amyloid (Abeta) peptide fibrils range from regarding them as the cause of Alzheimer's pathology to having a protective function. In the last few years, it has also been suggested that soluble oligomers might be the most important toxic species. In all cases, the study of the conformational properties of Abeta peptides in soluble form constitutes a basic approach to the design of molecules with "antiamyloid" activity. We have experimentally investigated the conformational path that can lead the Abeta-(1-42) peptide from the native state, which is represented by an alpha helix embedded in the membrane, to the final state in the amyloid fibrils, which is characterized by beta-sheet structures. The conformational steps were monitored by using CD and NMR spectroscopy in media of varying polarities. This was achieved by changing the composition of water and hexafluoroisopropanol (HFIP). In the presence of HFIP, beta conformations can be observed in solutions that have very high water content (up to 99 % water; v/v). These can be turned back to alpha helices simply by adding the appropriate amount of HFIP. The transition of Abeta-(1-42) from alpha to beta conformations occurs when the amount of water is higher than 80 % (v/v). The NMR structure solved in HFIP/H2O with high water content showed that, on going from very apolar to polar environments, the long N-terminal helix is essentially retained, whereas the shorter C-terminal helix is lost. The complete conformational path was investigated in detail with the aid of molecular-dynamics simulations in explicit solvent, which led to the localization of residues that might seed beta conformations. The structures obtained might help to find regions that are more affected by environmental conditions in vivo. This could in turn aid the design of molecules able to inhibit fibril deposition or revert oligomerization processes.

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Section: Discussionmentioning

confidence: 99%

The α‐to‐β Conformational Transition of Alzheimer's Aβ‐(1–42) Peptide in Aqueous Media is Reversible: A Step by Step Conformational Analysis Suggests the Location of β Conformation Seeding

et al. 2006

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“…The stability and function of proteins, as well as many biological processes, are dependent on the environmental pH; examples include fibril formation of amyloid peptides and prion proteins (Clippingdale et al, 2001;Kelly, 1997), membrane fusion of influenza virus (Bullough et al, 1994), and proton gradient-driven ATP synthesis (Rastogi and Girvin, 1999). Conventional MD simulations use predefined protonation states of the protein, making it difficult to explore such pH-coupled biological phenomena.…”

Section: Constant Ph Molecular Dynamicsmentioning

confidence: 99%

Peptide and Protein Folding and Conformational Equilibria: Theoretical Treatment of Electrostatics and Hydrogen Bonding with Implicit Solvent Models

Chen

Brooks

2005

Advances in Protein Chemistry

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“…2 is a progressive and fatal brain disorder affecting as many as 6 million Americans, yet there are currently no effective treatments targeting the underlying molecular cause of this debilitating neurodegenerative disease (1)(2)(3)(4)(5). Pathologically, the AD brain at its end stage is characterized by atrophy of the hippocampus and cerebral cortex, as well as accumulation of extracellular proteinaceous insoluble plaques composed of amyloid, a fibrillar form of protein.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%