Pathogenic Protein Seeding in Alzheimer Disease and Other Neurodegenerative Disorders

Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Annals of Neurology (Impact Factor: 11.91). 10/2011; 70(4):532-40. DOI: 10.1002/ana.22615
Source: PubMed

ABSTRACT The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism-corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.

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    • "Therefore, identification of aggregation-forming fragments is helpful for elucidating mechanisms of protein aggregation and designing antiaggregation inhibitors [14]. As we know, X-ray scattering, nuclear magnetic resonance or electron microscopy [15] are common experimental approaches used to observe the structural features of proteins. However, separation and purification of proteins commonly requires complicated parameters, and is a very time, resource, and found consuming process [16]. "
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    ABSTRACT: It is essential to predict aggregation-forming sequences for elucidation of protein misfolding mechanisms and the design of effective antiamyloid inhibitors. In this work, we predict and characterize self-assembled hexapeptides by a quantitative sequence-aggregation relationship (QSAR) model, which involves characterization of factor analysis scale of generalized amino acid information (FASGAI) and modeling of supporting vector machine (SVM) with radial basis function kernel. The QSAR model achieves maximum accuracy of 78.33% and area under the receiver operating characteristic curve of 0.83 with leave one out cross-validation on 180 training hexapeptides. We determine "hotspots" and key factors that largely contribute to the self-assembly of these hexapeptides by analyzing their sequence-aggregation relationships. We also explore the applications of the present model, e.g., the first is to identify the aggregation-forming sequences within both β-amyloid peptide (Aβ42) and human islet amyloid polypeptide (hIAPP) using a 6-residue slide window, and acquire good agreement with previous experimental observations, the second is to perform in silico design of potential aggregation-forming hexapeptides which are validated by all-atom molecular dynamics simulation and density functional theory calculations, and the third is to predict the potential self-assembled tri-, tetra- and pentapeptides, in which hydrophobic amino acids such as isoleucine, leucine, valine, phenylalanine, and methionine occur at higher frequencies. The present QSAR model is helpful for (i) predicting self-assembled behaviors of peptides, (ii) scanning and identifying aggregation-forming sequences within proteins, (iii) understanding action mechanisms of peptide/protein aggregation, and (iv) designing potential self-assembled sequences applied as drug discovery and nano-materials.
    Chemometrics and Intelligent Laboratory Systems 04/2015; 145. DOI:10.1016/j.chemolab.2015.04.009 · 2.32 Impact Factor
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    • "Both Ab and tau oligomers have similar but not identical structural and biophysical properties, including a high b sheet content , some resistance to proteolytic degradation, and neuronal toxicity. Recent work also has revealed that Ab-and tau-related pathology can, in certain scenarios, ''seed'' or transmit each other (Ashe and Aguzzi, 2013; Jucker and Walker, 2011). Existing therapies have either no or minimal disease-modifying benefit. "
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    ABSTRACT: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. It is characterized by an imbalance between production and clearance of amyloid β (Aβ) and tau proteins. Oligomeric forms of Aβ and tau are believed to be the most toxic. Dramatic results from AD animal models showed great promise for active and passive immune therapies targeting Aβ. However, there is very limited evidence in human studies of the clinical benefits from these approaches. Immunotherapies targeting only tau pathology have had some success but are limited so far to mouse models. The majority of current methods is based on immunological targeting of a self-protein; hence, benefits need to be balanced against risks of stimulating excessive autoimmune toxic inflammation. For greater efficacy the next generation of vaccines needs to focus more on concurrently targeting all the intermediate toxic conformers of oligomeric Aβ and tau species. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 03/2015; 85(6):1162-1176. DOI:10.1016/j.neuron.2014.12.064 · 15.98 Impact Factor
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    • "The spatial propagation of these misfolded proteins would, therefore , explain the sequential symptomatic progression observed in the majority of the neurodegenerative diseases (Walker et al., 2002). Although in some experiments involving artificial injection of brain extracts from patients with AD into the brains of mice, the induction of β-amyloid deposits was initially most evident within the injected area, recent cross-sectional autopsy studies have demonstrated that the accumulation of misfolded proteins follows a characteristic and predictable pattern of spatial progression in the brain of patients affected by AD (Jucker and Walker, 2011; Figure 1). These findings confirm the results of earlier studies which have shown sequential progression of neurofibrillary degeneration from the phylogenetically older mesial temporal regions to temporal cortical regions and finally to several other neocortical areas (Delacourte et al., 1999). "
    Frontiers in Neurology 06/2013; 4:75. DOI:10.3389/fneur.2013.00075
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