Current Alzheimer Research

ISSN: 1567-2050

Current Alzheimer Research
Volume 5, Number 3, June 2008

Contents

The Structural Basis of Amyloid Formation
Guest Editors: Hermona Soreq and Ehud Gazit


Editorial: Pp. 232
Hermona Soreq and Ehud Gazit


Structure-Function Implications in Alzheimer's Disease: Effect of Aβ Oligomers at Central Synapses Pp. 233-243
Waldo Cerpa, Margarita C. Dinamarca and Nibaldo C. Inestrosa
[Abstract]


Role of the Region 23-28 in Aß Fibril Formation: Insights from Simulations of the Monomers and Dimers of Alzheimer’s Peptides Aβ40 and Aβ42 Pp. 244-250
Adrien Melquiond, Xiao Dong, Normand Mousseau and Philippe Derreumaux
[Abstract]


Assembly of the Asparagine- and Glutamine-Rich Yeast Prions into Protein Fibrils Pp. 251-259
Luc Bousset, Jimmy Savistchenko and Ronald Melki
[Abstract]


Amyloidogenesis of Natively Unfolded Proteins Pp. 260-287
Vladimir N. Uversky
[Abstract]


Fiber Diffraction As a Screen for Amyloid Inhibitors Pp . 288-307
Daniel A. Kirschner, Abby A. R. Gross, Marla M. Hidalgo, Hideyo Inouye, Katherine A. Gleason, George A. Abdelsayed, Gerardo M. Castillo, Alan D. Snow, Angela Pozo-Ramajo, Sarah A. Petty and Sean M. Decatur
[Abstract]


Structural Basis of Infectious and Non-Infectious Amyloids Pp. 308-318
Ulrich Baxa
[Abstract]


Structure–Function Relationships of Pre-Fibrillar Protein Assemblies in Alzheimer's Disease and Related Disorders Pp. 319-341
F. Rahimi, A. Shanmugam and G. Bitan
[Abstract]


General Article


Functional Consequences of Locus Coeruleus Degeneration in Alzheimer’s Disease Pp . 342-345
David Weinshenker
[Abstract]




Abstracts

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Editorial: The Structural Basis of Amyloid Formation


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Structure-Function Implications in Alzheimer's Disease: Effect of Aβ Oligomers at Central Synapses
Waldo Cerpa, Margarita C. Dinamarca and Nibaldo C. Inestrosa

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A characteristic of AD is the accumulation of plaques in the brain of AD patients, and theses plaques mainly consist of aggregates of amyloid β-peptide (Aβ). All converging lines of evidence suggest that progressive accumulation of the Aβ plays a central role in the genesis of Alzheimer’s disease and it was long understood that Aβ had to be assembled into extracellular amyloid fibrils to exert its cytotoxic effects. This process could be modulated by molecular chaperones which inhibit or accelerate the amyloid formation. The enzyme Acetylcholinesterase (AChE) induces Aβ fibrils formation, forming a stable complex highly neurotoxic. On the other hand, laminin inhibit the Aβ fibrils formation and depolymerizate Aβ fibrils also. Over the past decade, data have emerged from the use of several sources of Aβ (synthetic, cell culture, transgenic mice and human brain) to suggest that intermediate species called Aβ oligomers are also injurious. Accumulating evidence suggests that soluble forms of Aβ are indeed the proximate effectors of synapse loss and neuronal injury. On the other hand, the member of the Wnt signaling pathway, β-catenin was markedly reduced in AD patients carrying autosomal dominant PS-1. Also, neurons incubated with Aβ revealed a significant dose-dependent decrease in the levels of cytosolic β-catenin an effect which was reversed in cells co-incubated with increasing concentrations of lithium, an activator of Wnt signaling pathway. Wnt signaling blocks the behavioural impairments induced by hippocampal injection of Aβ, therefore the activation of Wnt signaling protects agains the Aβ neurotoxicity. Here we review recent progress about Aβ structure and function, from the formation of amyloid fibrils and some molecular chaperones which modulate the amyloidogenesic process to synaptic damage induce by Aβ oligomers.


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Role of the Region 23-28 in Aß Fibril Formation: Insights from Simulations of the Monomers and Dimers of Alzheimer’s Peptides Aβ40 and Aβ42
Adrien Melquiond, Xiao Dong, Normand Mousseau and Philippe Derreumaux

Self-assembly of the 40/42 amino acid Aβ peptide is a key player in Alzheimer’s disease. Aβ40 is the most prevalent species, while Aβ42 is the most toxic. It has been suggested that the amino acids 21-30 could nucleate the folding of Aβ monomer and a bent in this region could be the rate-limiting step in Aβ fibril formation. In this study, we review our current understanding of the computer-predicted conformations of amino acids 23-28 in the monomer of Aβ(21-30) and the monomers Aβ40 and Aβ42. On the basis of new simulations on dimers of full-length Aβ, we propose that the rate-limiting step involves the formation of a multimeric β-sheet spanning the central hydrophobic core (residues 17-21).


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Assembly of the Asparagine- and Glutamine-Rich Yeast Prions into Protein Fibrils
Luc Bousset, Jimmy Savistchenko and Ronald Melki

The proteins Ure2, Sup35 and Rnq1 from the baker’s yeast have infectious properties, termed prions, at the origin of heritable and transmissible phenotypic changes. It is widely believed that prion properties arise from the assembly of Ure2p, Sup35p and Rnq1p into insoluble fibrils.

Yeast prions possess regions crucial for their propagation that can be either N- or C-terminal. These regions have unusual amino acid composition. They are very rich in glutamine and asparagine residues and resemble in that to huntingtin, a protein involved in the neurodegenerative Huntington’s disease.

Yeast prions assembly process has been hypothesized to be the consequence of the properties of glutamines and asparagines to engage in polar protein-protein interactions, termed polar-zippers. While this can certainly occur under certain conditions, glutamine and asparagine residues can establish other kinds of interactions with a variety of amino acid residues thus mediating protein-protein interactions involved in the assembly of polypeptide chains into high molecular weight oligomers.

This review details the interactions that can be established by glutamine and asparagine residues that may allow a better understanding of their role in mediating protein-protein interactions and prion propagation.


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Amyloidogenesis of Natively Unfolded Proteins
Vladimir N. Uversky

Aggregation and subsequent development of protein deposition diseases originate from conformational changes in corresponding amyloidogenic proteins. The accumulated data support the model where protein fibrillogenesis proceeds via the formation of a relatively unfolded amyloidogenic conformation, which shares many structural properties with the pre-molten globule state, a partially folded intermediate first found during the equilibrium and kinetic (un)folding studies of several globular proteins and later described as one of the structural forms of natively unfolded proteins. The flexibility of this structural form is essential for the conformational rearrangements driving the formation of the core cross-beta structure of the amyloid fibril. Obviously, molecular mechanisms describing amyloidogenesis of ordered and natively unfolded proteins are different. For ordered protein to fibrillate, its unique and rigid structure has to be destabilized and partially unfolded. On the other hand, fibrillogenesis of a natively unfolded protein involves the formation of partially folded conformation; i.e., partial folding rather than unfolding. In this review recent findings are surveyed to illustrate some unique features of the natively unfolded proteins amyloidogenesis.


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Fiber Diffraction As a Screen for Amyloid Inhibitors
Daniel A. Kirschner, Abby A. R. Gross, Marla M. Hidalgo, Hideyo Inouye, Katherine A. Gleason, George A. Abdelsayed, Gerardo M. Castillo, Alan D. Snow, Angela Pozo-Ramajo, Sarah A. Petty and Sean M. Decatur

Targeting the initial formation of amyloid assemblies is a preferred approach to therapeutic intervention in amyloidoses, which include such diseases as Alzheimer’s, Parkinson’s, Huntington’s, etc., as the early-stage, oligomers that form before the development of β-conformation-rich fibers are thought to be toxic. X-ray patterns from amyloid assemblies always show two common intensity maxima: one at 4.7 Å corresponding to the hydrogen-bonding spacing between the β-chains, and the other at ~10 Å corresponding to the spacing between β-pleated sheets. We report here the application of fiber x-ray diffraction to monitor these structural indicators of amyloid fiber assembly in the presence of small, aromatic molecules, some of which have been assessed by other techniques as being inhibitory. The compounds included butylated hydroxytoluene, chloramphenicol, cotinine, curcumin, diphenylalanine (FF), ethyl 3-aminobenzoate methane sulfonate, hexachlorophene, melatonin, methylpyrrolidine, morin, nicotine, phenolphthalaine, PTI-00703^® (Cat's claw), pyridine, quinine, sulfadiazine, tannic acid, tetracaine, tetrachlorosalicylanilide, and tetracycline. Their effects on the aggregation of Aβ1-40, Aβ11-25, Aβ12-28, Aβ17-28, Aβ16-22, and Aβ16-22[methylated] analogues were characterized in terms of the integral widths and integrated intensities of the two characteristic reflections.

Peptide Aβ11-25 with or without small molecules showed varying relative intensities but similar coherent lengths of 28–49 Å in the intersheet and 171–221 Å in the H-bonding directions. PTI-00703^®, however, abolished the H-bonding reflection. Among previously reported aromatic inhibitors for Aβ11-25, PTI-00703^®, tannic acid, and quinine were more effective than curcumin, morin, and melatonin based on the criterion of crystallite volume. For the N-methylated and control samples, there were no substantial differences in spacings and coherent lengths; however, the relative volumes of the β-crystallites, which were calculated from the magnitude of the intensities, decreased with increase in concentration of Aβ16-22Me. This may be accounted for by the binding of Aβ16-22Me to the monomer or preamyloid oligomer of Aβ16-22. The fiber diffraction approach, which can help to specify whether an amyloidophilic compound acts by impeding hydrogen-bonding or by altering intersheet interactions, may help provide a rationale basis for the development of other therapeutic reagents.


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Structural Basis of Infectious and Non-Infectious Amyloids
Ulrich Baxa

Amyloid fibrils are elongated protein aggregates well known for their association with many human diseases. However, similar structures have also been found in other organisms and amyloid fibrils can also be formed in vitro by other proteins usually under non-physiological conditions. In all cases, these fibrils assemble in a nucleated polymerization reaction with a pronounced lag phase that can be eliminated by supplying pre-formed fibrils as seeds. Once formed, the fibrils are usually very stable, except for their tendency to break into smaller pieces forming more growing ends in the process. These properties give amyloid fibers a self-replicating character dependent only on a source of soluble protein. For some systems and under certain circumstances this can lead to infectious protein structures, so-called prions, that can be passed from one organism to another as in the transmissible spongiform encephalopathies and in fungal prion systems. Structural details about these processes have emerged only recently, mostly on account of the inability of traditional high-resolution methods to deal with insoluble, filamentous specimens. In consequence, current models for amyloid fibrils are based on fewer constraints than common atomic-resolution structures. This review gives an overview of the constraints used for the development of amyloid models and the methods used to derive them. The principally possible structures will be introduced by discussing current models of amyloid fibrils from Alzheimer’s β-peptide, amylin and several fungal systems. The infectivity of some amyloids under specific conditions might not be due to a principal structural difference between infectious and non-infectious amyloids, but could result from an interplay of the rates for filament nucleation, growth, fragmentation, and clearance .


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Structure–Function Relationships of Pre-Fibrillar Protein Assemblies in Alzheimer's Disease and Related Disorders
F. Rahimi, A. Shanmugam and G. Bitan

Several neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and prion diseases, are characterized pathognomonically by the presence of intra- and/or extracellular lesions containing proteinaceous aggregates, and by extensive neuronal loss in selective brain regions. Related non-neuropathic systemic diseases, e.g., light-chain and senile systemic amyloidoses, and other organ-specific diseases, such as dialysis-related amyloidosis and type-2 diabetes mellitus, also are characterized by deposition of aberrantly folded, insoluble proteins. It is debated whether the hallmark pathologic lesions are causative. Substantial evidence suggests that these aggregates are the end state of aberrant protein folding whereas the actual culprits likely are transient, pre-fibrillar assemblies preceding the aggregates. In the context of neurodegenerative amyloidoses, the proteinaceous aggregates may eventuate as potentially neuroprotective sinks for the neurotoxic, oligomeric protein assemblies. The pre-fibrillar, oligomeric assemblies are believed to initiate the pathogenic mechanisms that lead to synaptic dysfunction, neuronal loss, and disease-specific regional brain atrophy.

The amyloid β-protein (Aβ), which is believed to cause Alzheimer's disease (AD), is considered an archetypal amyloidogenic protein. Intense studies have led to nominal, functional, and structural descriptions of oligomeric Aβ assemblies. However, the dynamic and metastable nature of Aβ oligomers renders their study difficult. Different results generated using different methodologies under different experimental settings further complicate this complex area of research and identification of the exact pathogenic assemblies in vivo seems daunting.

Here we review structural, functional, and biological experiments used to produce and study pre-fibrillar Aβ assemblies, and highlight similar studies of proteins involved in related diseases. We discuss challenges that contemporary researchers are facing and future research prospects in this demanding yet highly important field.


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Functional Consequences of Locus Coeruleus Degeneration in Alzheimer’s Disease
David Weinshenker

Alzheimer's disease (AD) is the most common cause of cognitive impairment in older patients, and its prevalence is expected to soar in coming decades. Neuropathologically, AD is characterized by beta-amyloid–containing plaques, tau-containing neurofibrillary tangles, and cholinergic neuronal loss. In addition to the hallmark of memory loss, the disease is associated with other neuropsychiatric and behavioral abnormalities, including psychosis, aggression, and depression. Although cholinergic cell loss is clearly an important attribute of the pathological process, another well-described yet underappreciated early feature of AD pathogenesis is degeneration of the locus coeruleus (LC), which serves as the main source of norepinephrine (NE) supplying various cortical and subcortical areas that are affected in AD. The purpose of this review is to explore the extent to which LC loss contributes to AD neuropathology and cognitive deficits.