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BBA - Biomembranes (v.1768, #8)

Editorial Board (pp. ii).

Preface to the special issue on amyloidogenic protein–membrane interaction by Katsumi Matsuzaki (pp. 1861-1861).

Fluorescence as a method to reveal structures and membrane-interactions of amyloidogenic proteins by Larissa A. Munishkina; Anthony L. Fink (pp. 1862-1885).

Amyloidogenesis is a characteristic feature of the 40 or so known protein deposition diseases, and accumulating evidence strongly suggests that self-association of misfolded proteins into either fibrils, protofibrils, or soluble oligomeric species is cytotoxic. The most likely mechanism for toxicity is through perturbation of membrane structure, leading to increased membrane permeability and eventual cell death. There have been a rather limited number of investigations of the interactions of amyloidogenic polypeptides and their aggregated states with membranes; these are briefly reviewed here. Amyloidogenic proteins discussed include A-beta from Alzheimer's disease, the prion protein, α-synuclein from Parkinson's disease, transthyretin (FAP, SSA amyloidosis), immunoglobulin light chains (primary (AL) amyloidosis), serum amyloid A (secondary (AA) amyloidosis), amylin or IAPP (Type 2 diabetes) and apolipoproteins. This review highlights the significant role played by fluorescence techniques in unraveling the nature of amyloid fibrils and their interactions and effects on membranes. Fluorescence spectroscopy is a valuable and versatile method for studying the complex mechanisms of protein aggregation, amyloid fibril formation and the interactions of amyloidogenic proteins with membranes. Commonly used fluorescent techniques include intrinsic and extrinsic fluorophores, fluorescent probes incorporated in the membrane, steady-state and lifetime measurements of fluorescence emission, fluorescence correlation spectroscopy, fluorescence anisotropy and polarization, fluorescence resonance energy transfer (FRET), fluorescence quenching, and fluorescence microscopy.

Keywords: Amyloid; Fibrils; Fluorescence probes; Oligomers; Protofibrils; Membrane permeability; Aggregation; Toxicity; Fluorescence resonance energy transfer; Fluorescence correlation spectroscopy; Fluorescence anisotropy

Dimethylsulfoxide-quenched hydrogen/deuterium exchange method to study amyloid fibril structure by Masaru Hoshino; Hidenori Katou; Kei-ichi Yamaguchi; Yuji Goto (pp. 1886-1899).

A general method to analyze the structure of a supramolecular complex of amyloid fibrils at amino acid residue resolution has been developed. This method combines the NMR-detected hydrogen/deuterium (H/D) exchange technique to detect hydrogen-bonded amide groups and the ability of the aprotic organic solvent dimethylsulfoxide (DMSO) to dissolve amyloid fibrils into NMR-observable, monomeric components while suppressing the undesired H/D exchange reaction. Moreover, this method can be generally applied to amyloid fibrils to elucidate the distribution of hydrogen-bonded amino acid residues in the three-dimensional molecular organization in the amyloid fibrils. In this study, we describe theoretical considerations in the H/D exchange method to obtain the structural information of proteins, and the DMSO-quenched H/D exchange method to study a supramolecular complex of amyloid fibrils. A possible application of this method to study the interaction of a protein/peptide with phospholipid membrane is also discussed.

Keywords: Hydrogen/deuterium exchange; Amyloid fibril; Nuclear magnetic resonance; Protein structure; Hydrogen bond

Solid-state NMR as a method to reveal structure and membrane-interaction of amyloidogenic proteins and peptides by Akira Naito; Izuru Kawamura (pp. 1900-1912).

It is important to understand the Amyloid fibril formation in view of numerous medical and biochemical aspects. Structural determination of amyloid fibril has been extensively studied using electron microscopy. Subsequently, solid state NMR spectroscopy has been realized to be the most important means to determine not only microscopic molecular structure but also macroscopic molecular packing. Molecular structure of amyloid fibril was first predicted to be parallel β-sheet structure, and subsequently, was further refined for Aβ(1–40) to be cross β-sheet with double layered in register parallel β-sheet structure by using solid state NMR spectroscopy. On the other hand, anti-parallel β-sheet structure has been reported to short fragments of Aβ-amyloid and other amyloid forming peptides. Kinetic study of amyloid fibril formation has been studied using a variety of methods, and two-step autocatalytic reaction mechanism used to explain fibril formation. Recently, stable intermediates or proto-fibrils have been observed by electron microscope (EM) images. Some of the intermediates have the same microscopic structure as the matured fibril and subsequently change to matured fibrils. Another important study on amyloid fibril formation is determination of the interaction with lipid membranes, since amyloid peptide are cleaved from amyloid precursor proteins in the membrane interface, and it is reported that amyloid lipid interaction is related to the cytotoxicity. Finally it is discussed how amyloid fibril formation can be inhibited. Firstly, properly designed compounds are reported to have inhibition ability of amyloid fibril formation by interacting with amyloid peptide. Secondly, it is revealed that site directed mutation can inhibit amyloid fibril formation. These inhibitors were developed by knowing the fibril structure determined by solid state NMR.

Keywords: Solid-state NMR; Amyloidogenic protein; Amyloid fibril; β-sheet; Cross β-sheet; Amyloid lipid interaction

A mechanistic link between oxidative stress and membrane mediated amyloidogenesis revealed by infrared spectroscopy by Hiroaki Komatsu; Liu Liu; Ian V.J. Murray; Paul H. Axelsen (pp. 1913-1922).

The fully developed lesion of Alzheimer's disease is a dense plaque composed of fibrillar amyloid β-proteins (Aβ) with a characteristic and well-ordered β-sheet secondary structure. Because the incipient lesion most likely develops when these proteins are first induced to form β-sheet structure, it is important to understand factors that induced Aβ to adopt this conformation. In this review, we describe the application of polarized attenuated total internal reflection infrared FT-IR spectroscopy for characterizing the conformation, orientation, and rate of accumulation of Aβ on lipid membranes. We also describe the application and yield of linked analysis, whereby multiple spectra are fit simultaneously with component bands that are constrained to share common fitting parameters. Results have shown that membranes promote β-sheet formation under a variety of circumstances that may be significant to the pathogenesis of Alzheimer's disease.

Keywords: Abbreviations; AD; Alzheimer's disease; Aβ; amyloid β proteins; Aβ40; 40-residue Aβ; Aβ42; 42-residue Aβ; PATIR-FTIR; polarized attenuated total internal reflection-Fourier transform infrared; ATIR-FTIR; unpolarized attenuated total internal reflection-Fourier transform infrared; IR; infrared; DTPA; diethylenetriaminepentaacetic acid; MRM-ESI-LC/MS/MS; multiple reaction monitoring electrospray ionization liquid chromatography tandem mass spectrometry; SAPC; 1-stearoyl-2-arachidonyl phosphatidylcholine; DMPC; dimyristoyl phosphatidylcholine; BHT; butylated hydroxytoluene; GM; ₁; Ganglioside GM; ₁; HNE; 4-hydroxy-2-nonenal; SAPCOX; oxidized SAPC

Kinetics of amyloid formation and membrane interaction with amyloidogenic proteins by Regina M. Murphy (pp. 1923-1934).

Interest in amyloidogenesis has exploded in recent years, as scientists recognize the role of amyloid protein aggregates in degenerative diseases such as Alzheimer's and Parkinson's disease. Assembly of proteins or peptides into mature amyloid fibrils is a multistep process initiated by conformational changes, during which intermediate aggregation states such as oligomers, protofibrils, and filaments are sampled. Although once it was assumed that the mature fibril was the biologically toxic species, more recently it has been widely speculated that soluble intermediates are the most damaging. Because of its relevance to mechanism of disease, the paths traversed during fibrillogenesis, and the kinetics of the process, are of considerable interest. In this review we discuss various kinetic models used to describe amyloidogenesis. Although significant advances have been made, construction of rigorous, detailed, and experimentally validated quantitative models remains a work in progress. We briefly review recent literature that illustrates the interplay between kinetics and amyloid–membrane interactions: how do different intermediates interact with lipid bilayers, and how does the lipid bilayer affect kinetics of amyloidogenesis?

Keywords: Kinetic; Amyloid; Beta-amyloid; Fibril; Lipid bilayer

Physicochemical interactions of amyloid β-peptide with lipid bilayers by Katsumi Matsuzaki (pp. 1935-1942).

The aggregation and deposition onto neuronal cells of amyloid β-peptide (Aβ) is central to the pathogenesis of Alzheimer's disease. Accumulating evidence suggests that membranes play a catalytic role in the aggregation of Aβ. This article summarizes the structures and properties of Aβ in solution and the physicochemical interaction of Aβ with lipid bilayers of various compositions. Reasons for discrepancies between results by different research groups are discussed. The importance of ganglioside clusters in the aggregation of Aβ is emphasized. Finally, a hypothetical physicochemical cascade in the pathogenesis of the disease is proposed.

Keywords: Abbreviations; Aβ; amyloid β-peptide; AD; Alzheimer's disease; APP; amyloid precursor protein; CD; circular dichroism; DAC-Aβ; Aβ-(1–40) with the diethylaminocoumarin dye at the N-terminus; L/P; lipid-to-peptide ratio; GSL; glycosphingolipids; PC; phosphatidylcholine; PG; phosphatidylglycerol; PI; phosphatidylinositol; PS; phosphatidylserine; SM; sphingomyelinAlzheimer's disease; Amyloid β-peptide; Lipid bilayer; Lipid raft; Ganglioside; Fibril formation

Role of gangliosides in Alzheimer’s disease by Katsuhiko Yanagisawa (pp. 1943-1951).

One of the fundamental questions regarding the pathogenesis of Alzheimer’s disease (AD) is how the monomeric, nontoxic amyloid β-protein (Aβ) is converted to its toxic assemblies in the brain. A unique Aβ species was identified previously in an AD brain, which is characterized by its binding to the GM1 ganglioside (GM1). On the basis of the molecular characteristics of this GM1-bound Aβ (GAβ), it was hypothesized that Aβ adopts an altered conformation through its binding to GM1, and GAβ acts as a seed for Aβ fibrillogenesis in an AD brain. To date, various in vitro and in vivo studies of GAβ have been performed, and their results support the hypothesis. Using a novel monoclonal antibody specific to GAβ, it was confirmed that GAβ is endogenously generated in the brain. Regarding the role of gangliosides in the facilitation of Aβ assembly, it has recently been reported that region-specific deposition of hereditary variant-type Aβs is determined by local gangliosides in the brain. Furthermore, it is likely that risk factors for AD, including aging and the expression of apolipoprotein E4, alter GM1 distribution on the neuronal surface, leading to GAβ generation.

Keywords: Alzheimer’s disease; Amyloid β-protein; Seed; Ganglioside; Cholesterol

Aβ ion channels. Prospects for treating Alzheimer's disease with Aβ channel blockers by Nelson Arispe; Juan C. Diaz; Olga Simakova (pp. 1952-1965).

The main pathological features in the Alzheimer’s brain are progressive depositions of amyloid protein plaques among nerve cells, and neurofibrillary tangles within the nerve cells. The major components of plaques are Aβ peptides. Numerous reports have provided evidence that Aβ peptides are cytotoxic and may play a role in the pathogenesis of AD. An increasing number of research reports support the concept that the Aβ–membrane interaction event may be followed by the insertion of Aβ into the membrane in a structural configuration which forms an ion channel. This review summarizes experimental procedures which have been designed to test the hypothesis that the interaction of Aβ with a variety of membranes, both artificial and natural, results in the subsequent formation of Aβ ion channels We describe experiments, by ourselves and others, that support the view that Aβ is cytotoxic largely due to the action of Aβ channels in the cell membrane. The interaction of Aβ with the surface of the cell membrane may results in the activation of a chain of processes that, when large enough, become cytotoxic and induce cell death by apoptosis. Remarkably, the blockage of Aβ ion channels at the surface of the cell absolutely prevents the activation of these processes at different intracellular levels, thereby preserving the life of the cells. As a prospect for therapy for Alzheimer’s disease, our findings at cellular level may be testable on AD animal models to elucidate the potential role and the magnitude of the contribution of the Aβ channels for induction of the disease.

Amyloid beta ion channel: 3D structure and relevance to amyloid channel paradigm by Ratnesh Lal; Hai Lin; Arjan P. Quist (pp. 1966-1975).

Alzheimer's disease (AD) is a protein misfolding disease. Early hypothesis of AD pathology posits that 39–43 AA long misfolded amyloid beta (Aβ) peptide forms a fibrillar structure and induces pathophysiological response by destabilizing cellular ionic homeostasis. Loss of cell ionic homeostasis is believed to be either indirectly due to amyloid beta-induced oxidative stress or directly by its interaction with the cell membrane and/or activating pathways for ion exchange. Significantly though, no Aβ specific cell membrane receptors are known and oxidative stress mediated pathology is only partial and indirect. Most importantly, recent studies strongly indicate that amyloid fibrils may not by themselves cause AD pathology. Subsequently, a competing hypothesis has been proposed wherein amyloid derived diffusible ligands (ADDLs) that are large Aβ oligomers (∼>60 kDa), mediate AD pathology. No structural details, however, of these large globular units exist nor is there any known suitable mechanism by which they would induce AD pathology. Experimental data indicate that they alter cell viability by non-specifically changing the plasma membrane stability and increasing the overall ionic leakiness. The relevance of this non-specific mechanism for AD-specific pathology seems limited. Here, we provide a viable new paradigm: AD pathology mediated by amyloid ion channels made of small Aβ oligomers (trimers to octamers). This review is focused to 3D structural analysis of the Aβ channel. The presence of amyloid channels is consistent with electrophysiological and cell biology studies summarized in companion reviews in this special issue. They show ion channel-like activity and channel-mediated cell toxicity. Amyloid ion channels with defined gating and pharmacological agents would provide a tangible target for designing therapeutics for AD pathology.

Keywords: Amyloid beta; Ion channel; 3D structure; Membrane-associated conformations; Channel mediated cell degeneration

The redox chemistry of the Alzheimer's disease amyloid β peptide by Danielle G. Smith; Roberto Cappai; Kevin J. Barnham (pp. 1976-1990).

There is a growing body of evidence to support a role for oxidative stress in Alzheimer's disease (AD), with increased levels of lipid peroxidation, DNA and protein oxidation products (HNE, 8-HO-guanidine and protein carbonyls respectively) in AD brains. The brain is a highly oxidative organ consuming 20% of the body's oxygen despite accounting for only 2% of the total body weight. With normal ageing the brain accumulates metals ions such iron (Fe), zinc (Zn) and copper (Cu). Consequently the brain is abundant in antioxidants to control and prevent the detrimental formation of reactive oxygen species (ROS) generated via Fenton chemistry involving redox active metal ion reduction and activation of molecular oxygen. In AD there is an over accumulation of the Amyloid β peptide (Aβ), this is the result of either an elevated generation from amyloid precursor protein (APP) or inefficient clearance of Aβ from the brain. Aβ can efficiently generate reactive oxygen species in the presence of the transition metals copper and iron in vitro. Under oxidative conditions Aβ will form stable dityrosine cross-linked dimers which are generated from free radical attack on the tyrosine residue at position 10. There are elevated levels of urea and SDS resistant stable linked Aβ oligomers as well as dityrosine cross-linked peptides and proteins in AD brain. Since soluble Aβ levels correlate best with the degree of degeneration [C.A. McLean, R.A. Cherny, F.W. Fraser, S.J. Fuller, M.J. Smith, K. Beyreuther, A.I. Bush, C.L. Masters, Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease, Ann. Neurol. 46 (1999) 860–866] we suggest that the toxic Aβ species corresponds to a soluble dityrosine cross-linked oligomer. Current therapeutic strategies using metal chelators such as clioquinol and desferrioxamine have had some success in altering the progression of AD symptoms. Similarly, natural antioxidants curcumin and ginkgo extract have modest but positive effects in slowing AD development. Therefore, drugs that target the oxidative pathways in AD could have genuine therapeutic efficacy.

Keywords: Amyloid beta; Metal; Oxidative stress; Redox chemistry; Alzheimer's disease

Amyloid beta-protein and lipid metabolism by Eva G. Zinser; Tobias Hartmann; Marcus O.W. Grimm (pp. 1991-2001).

Lipids play an important part as risk or protective factors for Alzheimer's disease. This review summarizes the current findings in which lipids influence Alzheimer's disease and introduces the molecular mechanism how these lipids are linked to amyloid production. Besides the pathological impact of amyloid in Alzheimer's disease, amyloid has a physiological function in regulating lipid homeostasis in return. The understanding of the resulting regulatory cycles between amyloid precursor protein processing and lipids provides a platform for the development of new causal therapeutic approaches for Alzheimer's disease.

Keywords: Alzheimer; Amyloid; Cholesterol; Sphingolipid; Raft; SREBP

Membrane interaction of islet amyloid polypeptide by Sajith A. Jayasinghe; Ralf Langen (pp. 2002-2009).

Increasing evidence suggests that the misfolding and deposition of IAPP plays an important role in the pathogenesis of type II, or non-insulin-dependent diabetes mellitus (T2DM). Membranes have been implicated in IAPP-dependent toxicity in several ways: Lipid membranes have been shown to promote the misfolding and aggregation of IAPP. Thus, potentially toxic forms of IAPP can be generated when IAPP interacts with cellular membranes. In addition, membranes have been implicated as the target of IAPP toxicity. IAPP has been shown to disrupt membrane integrity and to permeabilize membranes. Since disruption of cellular membranes is highly toxic, such a mechanism has been suggested to explain the observed IAPP toxicity. Here, we review IAPP–membrane interaction in the context of (1) catalyzing IAPP misfolding and (2) being a potential origin of IAPP toxicity.

Keywords: Islet amyloid polypeptide; IAPP; Membranes; Aggregation; Membrane damage

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BBA - Biomembranes (v.1768, #8)