Therapeutics in Alzheimer's and Prion Diseases

2002 ◽  
Vol 30 (4) ◽  
pp. 574-578 ◽  
Author(s):  
T. Wisniewski ◽  
D. R. Brown ◽  
E. M. Sigurdsson
Keyword(s):  
Protein Conformation ◽  
Prion Diseases ◽  
Amyloid Β ◽  
Experimental Manipulation ◽  
Critical Event ◽  
Amyloid Β Peptide ◽  
Immune System Activation ◽  
Amyloidogenic Protein ◽  
Associated Proteins ◽  
Β Sheet

There is increasing recognition that numerous neurodegenerative conditions have the same underlying pathogenetic mechanism, namely a change in protein conformation, where the β-sheet content is increased. In Alzheimer's disease, amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid-β peptide (sAβ) to Aβ plaques; while in the prionoses the critical event is the conversion of normal prion protein, PrPc, to the disease-associated form, PrPsc. This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. A number of different approaches under current development include drugs which affect the processing of the precursor proteins drugs the clearance of the amyloidogenic protein, and which inhibit or prevent the conformation change and immunological approaches. Particularly interesting are compounds termed ‘β-sheet breakers’ that directly target the abnormal conformational change both for Aβ- and PrPsc-related deposits. In addition, immune system activation can serve as β-sheet breakers and/or to increase the clearance of the disease-associated proteins. These conformation-based approaches appear to hold the best promise for therapies for this devastating group of disorders.

Apolipoprotein E includes a binding site which is recognized by several amyloidogenic polypeptides

2000 ◽  
Vol 349 (1) ◽  
pp. 77-84 ◽  
Author(s):  
Marc H. BAUMANN ◽  
Jukka KALLIJÄRVI ◽  
Hilkka LANKINEN ◽  
Claudio SOTO ◽  
Matti HALTIA
Keyword(s):  
Apolipoprotein E ◽  
Binding Site ◽  
Late Onset ◽  
Specific Binding ◽  
Prion Diseases ◽  
Amyloid Β ◽  
Structural Motif ◽  
Amyloid Β Peptide ◽  
High Avidity ◽  
Amyloidogenic Protein

Inheritance of the apolipoprotein E (apoE) ϵ4 allele is a risk factor for late-onset Alzheimer's disease (AD). Biochemically apoE is present in AD plaques and neurofibrillary tangles of the AD brain. There is a high avidity and specific binding of apoE and the amyloid β-peptide (Aβ). In addition to AD apoE is also present in many other cerebral and systemic amyloidoses, Down's syndrome and prion diseases but the pathophysiological basis for its presence is still unknown. In the present study we have compared the interaction of apoE with Aβ, the gelsolin-derived amyloid fragment AGel183-210 and the amyloidogenic prion fragments PrP109-122 and PrP109-141. We show that, similar to Aβ, also AGel and PrP fragments can form a complex with apoE, and that the interaction between apoE and the amyloidogenic protein fragments is mediated through the same binding site on apoE. We also show that apoE increases the thioflavin-T fluorescence of PrP and AGel and that apoE influences the content of β-sheet conformation of these amyloidogenic fragments. Our results indicate that amyloids and amyloidogenic prion fragments share a similar structural motif, which is recognized by apoE, possibly through a single binding site, and that this motif is also responsible for the amyloidogenicity of these fragments.

Modulation of amyloid β peptide aggregation by hydrophilic polymers

2019 ◽  
Vol 21 (37) ◽  
pp. 20999-21006
Author(s):  
Zhanna Evgrafova ◽  
Bruno Voigt ◽  
Andreas H. Roos ◽  
Gerd Hause ◽  
Dariush Hinderberger ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Hydrophilic Polymers ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation ◽  
Amyloidogenic Protein

Careful balance of hydrophilicity of precisely engineered polymers alters aggregation of the amyloidogenic protein Aβ1–40.

scholarly journals Prion protein and prion disease at a glance

2021 ◽  
Vol 134 (17) ◽  
Author(s):  
Caihong Zhu ◽  
Adriano Aguzzi
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Amyloid Β ◽  
Cellular Prion Protein ◽  
Future Studies ◽  
Associated Proteins ◽  
Main Component ◽  
Conformational Conversion

ABSTRACT Prion diseases are neurodegenerative disorders caused by conformational conversion of the cellular prion protein (PrPC) into scrapie prion protein (PrPSc). As the main component of prion, PrPSc acts as an infectious template that recruits and converts normal cellular PrPC into its pathogenic, misfolded isoform. Intriguingly, the phenomenon of prionoid, or prion-like, spread has also been observed in many other disease-associated proteins, such as amyloid β (Aβ), tau and α-synuclein. This Cell Science at a Glance and the accompanying poster highlight recently described physiological roles of prion protein and the advanced understanding of pathogenesis of prion disease they have afforded. Importantly, prion protein may also be involved in the pathogenesis of other neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Therapeutic studies of prion disease have also exploited novel strategies to combat these devastating diseases. Future studies on prion protein and prion disease will deepen our understanding of the pathogenesis of a broad spectrum of neurodegenerative conditions.

scholarly journals Identification of Novel γ-Secretase-associated Proteins in Detergent-resistant Membranes from Brain

2012 ◽  
Vol 287 (15) ◽  
pp. 11991-12005 ◽  
Author(s):  
Ji-Yeun Hur ◽  
Yasuhiro Teranishi ◽  
Takahiro Kihara ◽  
Natsuko Goto Yamamoto ◽  
Mitsuhiro Inoue ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Affinity Purification ◽  
Amyloid Β ◽  
Anion Channel ◽  
Amyloid Β Peptide ◽  
Voltage Dependent Anion Channel ◽  
App Processing ◽  
Associated Proteins ◽  
Detergent Resistant Membranes ◽  
Aβ Production

In Alzheimer disease, oligomeric amyloid β-peptide (Aβ) species lead to synapse loss and neuronal death. γ-Secretase, the transmembrane protease complex that mediates the final catalytic step that liberates Aβ from its precursor protein (APP), has a multitude of substrates, and therapeutics aimed at reducing Aβ production should ideally be specific for APP cleavage. It has been shown that APP can be processed in lipid rafts, and γ-secretase-associated proteins can affect Aβ production. Here, we use a biotinylated inhibitor for affinity purification of γ-secretase and associated proteins and mass spectrometry for identification of the purified proteins, and we identify novel γ-secretase-associated proteins in detergent-resistant membranes from brain. Furthermore, we show by small interfering RNA-mediated knockdown of gene expression that a subset of the γ-secretase-associated proteins, in particular voltage-dependent anion channel 1 (VDAC1) and contactin-associated protein 1 (CNTNAP1), reduced Aβ production (Aβ40 and Aβ42) by around 70%, whereas knockdown of presenilin 1, one of the essential γ-secretase complex components, reduced Aβ production by 50%. Importantly, these proteins had a less pronounced effect on Notch processing. We conclude that VDAC1 and CNTNAP1 associate with γ-secretase in detergent-resistant membranes and affect APP processing and suggest that molecules that interfere with this interaction could be of therapeutic use for Alzheimer disease.

Copper selectively triggers β-sheet assembly of an N-terminally truncated amyloid β-peptide beginning with Glu3

2004 ◽  
Vol 98 (1) ◽  
pp. 10-14 ◽  
Author(s):  
Takashi Miura ◽  
Sayoko Mitani ◽  
Chiho Takanashi ◽  
Nobuhiro Mochizuki
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Β Sheet

scholarly journals The antigen-binding fragment of human gamma immunoglobulin prevents amyloid β-peptide folding into β-sheet to form oligomers

Oncotarget ◽  
2017 ◽  
Vol 8 (25) ◽  
pp. 41154-41165 ◽  
Author(s):  
Victòria Valls-Comamala ◽  
Biuse Guivernau ◽  
Jaume Bonet ◽  
Marta Puig ◽  
Alex Perálvarez-Marín ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Peptide Folding ◽  
Antigen Binding ◽  
Amyloid Β Peptide ◽  
Β Sheet

scholarly journals Out-of-register parallel β-sheets and antiparallel β-sheets coexist in 150 kDa oligomers formed by Aβ(1-42)

2020 ◽  
Author(s):  
Yuan Gao ◽  
Cong Guo ◽  
Jens O. Watzlawik ◽  
Elizabeth J. Lee ◽  
Danting Huang ◽  
...  
Keyword(s):  
Solid State Nmr ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Dipolar Recoupling ◽  
Negative Results ◽  
Assembly Pathway ◽  
Fibril Structure ◽  
Proposed Model ◽  
Β Sheets ◽  
Β Sheet

AbstractWe present solid-state NMR measurements of β-strand secondary structure and inter-strand organization within a 150 kDa oligomeric aggregate of the 42-residue variant of the Alzheimer’s amyloid-β peptide (Aβ(1-42)). This oligomer is characterized by a structure that cannot be explained by any previously proposed model for aggregated Aβ. We build upon our previous report of a β-strand spanned by residues 30-42, which arranges into an antiparallel β-sheet. New results presented here indicate that there is a second β-strand formed by residues 11-24. We show negative results for NMR experiments designed to reveal antiparallel β-sheets formed by this β-strand. Remarkably, we show that this strand is organized into a parallel β-sheet despite the co-existence of an antiparallel β-sheet in the same structure. In addition, the in-register parallel β-sheet commonly observed for amyloid fibril structure does not apply to residues 11-24 in the 150 kDa oligomer. Rather, we present evidence for an inter-strand registry shift of 3 residues that alternates in direction between adjacent molecules along the β-sheet. We corroborated this unexpected scheme for β-strand organization using multiple 2-dimensional NMR and 13C-13C dipolar recoupling experiments. Our findings indicate a previously unknown assembly pathway and inspire a suggestion as to why this aggregate does not grow to larger sizes.

The prion-like properties of amyloid-beta peptide and Tau: Is there any risk of transmitting Alzheimer's disease during neurosurgical interventions?

2020 ◽  
Vol 17 ◽  
Author(s):  
Padilla-Zambrano H ◽  
García-Ballestas E ◽  
Quiñones-Ossa GA ◽  
Sibaja-Perez A ◽  
Agrawal A ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prion Diseases ◽  
Amyloid Β ◽  
Public Health Issue ◽  
Amyloid Β Peptide ◽  
Neurosurgical Procedure ◽  
Beta Peptide

: Recent studies have recognized similarities between the peptides involved in the neuropathology of Alzheimer’s disease and prions. The Tau protein and the Amyloid β peptide represent the theoretical pillars of Alzheimer’s disease development. It is probable that there is a shared mechanism for the transmission of these substances and the prion diseases development; this presumption is based on the presentation of several cases of individuals without risk factors who developed dementia decades after a neurosurgical procedure. This article aims to present the role of Aβ and Tau, which underlie the pathophysiologic mechanisms involved in the AD and their similarities with the prion diseases infective mechanisms by means of the presentation of the available evidence at molecular (in-vitro), animal, and human levels that support the controversy on whether these diseases might be transmitted in neurosurgical interventions, which may constitute a wide public health issue.

Drug targets for amyloidosis

2010 ◽  
Vol 38 (2) ◽  
pp. 466-470 ◽  
Author(s):  
Simon E. Kolstoe ◽  
Steve P. Wood
Keyword(s):  
Protein Misfolding ◽  
Drug Targets ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Transthyretin Amyloidosis ◽  
Amyloid Deposits ◽  
Aβ Amyloid ◽  
Amyloidogenic Protein ◽  
Cross Links ◽  
Ad Alzheimer’S Disease

The amyloid hypothesis indicates that protein misfolding is at the root of many neurodegenerative disorders. Small molecules targeting the formation, clearance, aggregation to toxic oligomers or SOD (superoxide dismutase)-like activities of Aβ (amyloid β-peptide) 1–42 have provided encouraging candidates for AD (Alzheimer's disease) medicines in animal models, although none have yet proved to be effective in human trials. We have been investigating approaches to treat systemic amyloidoses, conditions that show common features with some CNS (central nervous system) disorders. For TTR (transthyretin) amyloidosis, we are seeking small molecule compounds that stabilize the amyloidogenic protein and either prevent its structural transition to the crossed β fibres deposited in diseased tissues, or promote its clearance from circulation. Effective stabilizer compounds that simultaneously bind to both thyroxine-binding sites have been developed. A more generic approach involves targeting the plasma glycoprotein SAP (serum amyloid P component). This protein recognizes the misfolded polypeptide structures of amyloid deposits wherever they occur, and acts as a powerful anti-opsonin. We have developed a bivalent drug called CPHPC {(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid} that cross-links pairs of pentameric SAP molecules and causes their rapid elimination from the circulation. This strategy raises the prospect of encouraging natural mechanisms to clear amyloid and recent work suggests that this approach extends to the CNS.

scholarly journals Interference with Amyloid-β Nucleation by Transient Ligand Interaction

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2129 ◽  
Author(s):  
Tao Zhang ◽  
Jennifer Loschwitz ◽  
Birgit Strodel ◽  
Luitgard Nagel-Steger ◽  
Dieter Willbold
Keyword(s):  
Amyloid Β ◽  
Intrinsically Disordered Protein ◽  
Amyloid Β Peptide ◽  
Amino Acid Residues ◽  
Ligand Interaction ◽  
Drug Candidates ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
First Time ◽  
Β Sheet

Amyloid-β peptide (Aβ) is an intrinsically disordered protein (IDP) associated with Alzheimer’s disease. The structural flexibility and aggregation propensity of Aβ pose major challenges for elucidating the interaction between Aβ monomers and ligands. All-D-peptides consisting solely of D-enantiomeric amino acid residues are interesting drug candidates that combine high binding specificity with high metabolic stability. Here we characterized the interaction between the 12-residue all-D-peptide D3 and Aβ42 monomers, and how the interaction influences Aβ42 aggregation. We demonstrate for the first time that D3 binds to Aβ42 monomers with submicromolar affinities. These two highly unstructured molecules are able to form complexes with 1:1 and other stoichiometries. Further, D3 at substoichiometric concentrations effectively slows down the β-sheet formation and Aβ42 fibrillation by modulating the nucleation process. The study provides new insights into the molecular mechanism of how D3 affects Aβ assemblies and contributes to our knowledge on the interaction between two IDPs.

Sign in / Sign up

Export Citation Format

Share Document