Current Alzheimer Research - Volume 5, Issue 6, 2008

Full text available

Neurodegeneration is a complex and multifaceted process leading to many chronic diseased states. Neurodegenerative disorders include a number of different pathological conditions, like Alzheimer's and Parkinson's diseases, which share similar critical metabolic processes, such as protein aggregation, which could be affected by some metal ions. A huge number of reports indicate that, among putative aggravating factors, metal ions (Al, Zn, Cu, Fe) could specifically impair protein aggregation of Aβ, prion protein, ataxin, huntingtin, etc. and their oligomeric toxicity. While studying the molecular basis of these diseases, it has become clear that protein conformation plays a critical role in the pathogenic process. In this review, we will focus on Alzheimer's disease and on the role of metal ions, specifically aluminium, in affecting amyloid aggregation, oligomerization and toxicity.

The aim of this review is to show how the challenging problem of understanding the physico-chemical basis of protein misfolding and aggregation which are at the origin of plaque formation in amyloid pathologies can be successfully investigated with a combination of modern spectroscopic techniques and advanced first principle numerical simulations. Within the vast group of diseases (more than 20) characterized by extra-cellular deposition of fibrillar material and generically called Amyloidosis, we shall focus on the Alzheimer's disease, a progressive and devastating neurodegenerative pathology affecting an important fraction of the world aged population. Well identified peptides (the so called Aβ- peptides) undergo a misfolding process during the development of the disease. An important, but not yet fully elucidated, role appears to be played in these processes by transition metals (mainly copper and zinc) that have been observed to be present in large amounts in patient's neurological plaques. Starting from this observation, a number of interesting results concerning the structural properties of the relevant metalpeptide binding site, emerging from the interplay between X-ray Absorption Spectroscopy experiments, and ab initio molecular dynamics simulations of the Car-Parrinello type will be reported and discussed.

Multiple lines of evidence demonstrate that oxidative stress is an early event in Alzheimer's disease (AD), occurring prior to cytopathology, and therefore may play a key pathogenic role in AD. Oxidative stress not only temporally precedes the pathological lesions of the disease but also activates cell signaling pathways, which, in turn, contribute to lesion formation and, at the same time, provoke cellular responses such as compensatory upregulation of antioxidant enzymes found in vulnerable neurons in AD. In this review, we provide an overview of the evidence of oxidative stress and compensatory responses that occur in AD, particularly focused on potential sources of oxidative stress and the roles and mechanism of activation of stress-activated protein kinase pathways.

Alzheimer's disease (AD) is the most common form of dementia in the elderly, and is characterized by the deposition of extracellular amyloid plaques primarily composed of the β-amyloid peptide (Aβ). While these plaques define the pathology of AD, disease progression has been shown to correlate more closely with the level of synaptotoxicity induced by soluble Aβ oligomers. Recent evidence suggests that these oligomers are covalently crosslinked, possibly due to the interaction of Aβ with redox-active metal ions. These findings offer new avenues for the treatment and prevention of disease, by modulating metal binding or preventing the formation of neurotoxic Aβ oligomers. An understanding of the chemical nature of Aβ is also required to elucidate the synaptotoxic process or processes in AD, which have so far resisted explanation.

Amyloid β peptide (Aβ),42-residue peptide and its variations, is known to form amyloid fibrils in Alzheimer's disease. Solid-state NMR study reveals a parallel β-sheet structure in the Aβ fibrils. The atomic level structure of Aβ in aqueous environment, however, has not been determined, because of its tendency to aggregate. There are several reports that soluble forms of Aβ possess intrinsic neurotoxicity. It has recently become possible to determine the crystal structure of Aβ fragments in an aqueous solution without organic solvents and detergents using a fusion technique with a hyperthermophile protein. Aβ28-42 forms a β-conformation. This fusion technique enables us to obtain structural information at atomic resolution for amyloidogenic peptides in aqueous environments. This review describes our current knowledge on the Aβ conformation in aqueous environments and some viewpoints based on the knowledge.

It is widely accepted that Aβ42 aggregation is a central event in the pathogenesis of Alzheimer's disease. Aβ42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death and eventually dementia. There are a number of physiological molecules that can protect Aβ42 from aggregation. Promoting such protective molecules and mechanisms against Aβ42 aggregation may be a novel direction in AD drug discovery. One of the most striking protective molecules is none other than Aβ40, which inhibits Aβ42 aggregation in a specific and dosage dependent manner. Aβ40 is a critical, built-in mechanism against Aβ42 aggregation. A number of other molecules and mechanisms also inhibit Aβ42 aggregation, such as heat shock proteins, L-PGDS, heme and methionine oxidation. The relevance of these protective mechanisms to AD pathogenesis and intervention is discussed.

The amyloid cascade hypothesis is well known hypothesis describing the pathogenesis of Alzheimer's disease (AD). On the basis of this hypothesis, inhibition of amyloid β-protein (Aβ) generation and aggregation, enhancement of extracellular Aβ removal, and Aβ vaccination are currently under investigation. Intracellular Aβ may be even more important than extracellular Aβ, since intraneuronal Aβ accumulation commonly precedes extracellular Aβ deposition in several familial AD-related mutant presenilin 1-transgenic mice. Various pathogenic mechanisms involving intracellular Aβ such as mitochondrial toxicity, proteasome impairment and synaptic damage have been suggested. Recently, we have reported that cytosolic Aβ42 accumulation leads to p53 mRNA expression and p53-related apoptosis. It was also reported that a novel chaperone protein, Aβ-related death-inducing protein (AB-DIP), regulates nuclear localization of intracellular Aβ42. Therefore, intraneuronal Aβ represents an alternative therapeutic target. While inhibition of Aβ production and anti-Aβ immunotherapies are likely to attenuate both intraneuronal and extracellular Aβ toxicity, more specific antiintraneuronal Aβ therapies should be useful. The focus of this article is to review the pathogenic mechanisms involving intracellular Aβ and advocate intracellular Aβ as an important therapeutic target in AD.

Human post-mortem brain samples are excellent source material for the analysis of age-related disorders such as Alzheimer's disease (AD). Moreover, data obtained from cell culture- or mouse model-related experiments often need to be validated by using human tissue. In a variety of studies over the last few years, a huge list of genes or proteins with differential expression or abundance between AD-related and control tissue has been reported. However, highly important issues such as changes in post-mortem time, sex, age etc. of the patients have been rarely included in the analysis. In our study we examined human frontal brain samples of 10 AD patients vs. 10 unaffected controls using state-of-the-art two dimensional DIGE proteomics in order to analyze protein expression of up to 10,000 proteins in parallel. Data were analyzed using well established DIGE-software tool as well as an analysis of covariance model including the factor effects of group and sex and the covariable effects of age and post-mortem time. Within this study we report protein expression changes in AD vs. control human frontal brain samples without any influence of other parameters as well as expression changes depending on the parameters mentioned above. In fact, some proteins previously suggested a state of being dysregulated in AD vs. controls revealed age or sex-dependent regulation. Our analysis suggests the necessity of integrating additionally available covariables in comparative proteome studies of two different sets of human tissue.

The PrP propensity to adopt different structures is tightly linked to transmissible spongiform encephalopathies (TSE) which include Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scjeinker (GSS) and Kuru syndrome. In most cases, TSE is associated with the accumulation in the brain of an abnormally folded protease-resistant protein, PrP^Sc or PrPres, which is derived from a cellular host-encoded protease-sensitive conformer, designated PrP^C. The prion propagation in the brain is postulated to occur via a conformational change of PrP^C into the amyloidogenic form PrP^Sc, characterized by a high β sheet content. The characterization of PrPSC oligomers as well as their biological activity is currently an area of active research. Indeed, PrPSc structural diversity was proposed several years ago as a hypothesis to explain the origin of “prion strain” diversity. As prion pathologies belong to protein miss-assembly diseases, investigation of PrP conformational dynamics and, more precisely, oligomerization pathways exploration will help to acheave a better understanding of the pathological events at the molecular level.

Prion diseases are fatal neurodegenerative disorders related to the conformational alteration of the prion protein (PrPC) into a pathogenic and protease-resistant isoform PrPSc. PrPC is a cell surface glycoprotein expressed mainly in the central nervous system and despite numerous efforts to elucidate its physiological role, the exact biological function remains unknown. Many lines of evidences indicate that prion is a copper binding protein and thus involved in the copper metabolism. Prion protein is not expressed only in mammals but also in other species such as birds, reptiles and fishes. However, it is noteworthy to point out that prion diseases are only observed in mammals while they seem to be spared to other species. The chicken prion protein (chPrPC) shares about 30% of identity in its primary sequence with mammal PrPC. Both types of proteins have an N-terminal domain endowed with tandem amino acid repeats (PHNPGY in the avian protein, PHGGGWQ in mammals), followed by a highly conserved hydrophobic core. Furthermore, NMR studies have highlighted a similar globular domain containing three β-helices, one short 310-helix and a short antiparallel β-sheet. Despite this structural similarity, it should be noted that the normal isoform of mammalian PrPC is totally degraded by proteinase K, while avian PrPC is not, thereby producing N-terminal domain peptide fragments stable to further proteolysis. Notably, the hexarepeat domain is considered essential for protein endocytosis, and it is supposed to be the analogous copper-binding octarepeat region of mammalian prion proteins. The number of copper binding sites, the affinity and the coordination environment of metal ions are still matter of discussion for both mammal and avian proteins. In this review, we summarize the similarities and the differences between mammalian and avian prion proteins, as revealed by studies carried out on the entire protein and related peptide fragments, using a range of experimental and computational approaches. In addition, we report the metal-driven conformational alteration, copper binding modes and the superoxide dismutase-like (SOD-like) activity of the related copper(II) complexes.

Intracellular accumulation of filamentous tau proteins is a defining feature of neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and frontotemporal dementia with Parkinsonism linked to chromosome 17, all known collectively as tauopathies. Tau protein is a member of microtubule (MT)-associated proteins. Tau is a highly soluble and natively unfolded protein dominated by a random coil structure in solution. It is believed that aberrant modifications of tau, including phosphorylation, truncation, and conformational changes, induce filamentous aggregation. However, the mechanism underlying the conversion of tau protein from a soluble state to one of insoluble aggregates still remains elusive. The importance of tau aggregation intermediates (e.g. tau dimer, tau multimer, and granular tau oligomer) in disease pathogenesis was suggested by recent studies. Here, we review the latest developments in tracking the structural changes of tau protein and discuss the utility improving our understanding of tau aggregation pathway leading to human tauopathies.

A number of studies have demonstrated a role for transition metals and oxidative stress in the etiology of Parkinson’s disease (PD). Genetic and biochemical evidence also clearly links the protein alpha-synuclein (αSyn) to PD and a number of associated diseases. In these “synucleinopathies”, αSyn is deposited, often in oligomerized forms, as cytoplasmic inclusions known as Lewy bodies and Lewy neurites. αSyn cross-linking/oligomerization can occur via a number of processes, most stimulated by metal catalyzed oxidation (MCO). In PD, the increased sensitivity of midbrain neurons expressing high levels of oxidizable catecholamines may provide one clue to account for degeneration of these neurons. In other regions of the nervous system that develop Lewy body pathology, the mode of αSyn oligomerization is less clear. Thus, the relationship between αSyn and MCO, either direct or indirect, represents a particular concern for possible treatment of these various diseases.