scholarly journals The Nicastrin ectodomain adopts a highly thermostable structure

2011 ◽  
Vol 392 (11) ◽  
Author(s):  
Regina Fluhrer ◽  
Frits Kamp ◽  
Gudula Grammer ◽  
Brigitte Nuscher ◽  
Harald Steiner ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Streptomyces Griseus ◽  
Amyloid Β ◽  
Structural Data ◽  
Cd Spectroscopy ◽  
Amyloid Β Peptide ◽  
Type I ◽  
Transmembrane Glycoprotein ◽  
High Propensity ◽  
Receptor Family

Abstract Nicastrin is a type I transmembrane glycoprotein, which is part of the high molecular weight γ-secretase complex. γ-Secretase is one of the key players associated with the generation of Alzheimer's disease pathology, since it liberates the neurotoxic amyloid β-peptide. Four proteins Nicastrin, anterior pharynx-defective-1 (Aph-1), presenilin enhancer-2 (Pen-2) and Presenilin are essential to form the active γ-secretase complex. Recently it has been shown, that Nicastrin has a key function in stabilizing the mature γ-secretase complex and may also be involved in substrate recognition. So far no structural data for the Nicastrin ectodomain or any other γ-secretase component are available. We therefore used Circular Dichroism (CD) spectroscopy to demonstrate that Nicastrin, similar to its homologues, the Streptomyces griseus aminopeptidase (SGAP) and the transferrin receptor (TfR), adopts a thermostable secondary structure. Furthermore, the Nicastrin ectodomain has an exceptionally high propensity to refold after thermal denaturation. These findings provide evidence to further support the hypothesis that Nicastrin may share evolutionary conserved properties with the aminopeptidase and the transferrin receptor family.

Aggregation and neurotoxicity of α-synuclein and related peptides

2002 ◽  
Vol 30 (4) ◽  
pp. 559-565 ◽  
Author(s):  
O. M. A. EI-Agnaf ◽  
G. B. Irvine
Keyword(s):  
Electron Microscopy ◽  
Antioxidant Properties ◽  
Amyloid Β ◽  
Cd Spectroscopy ◽  
Amyloid Β Peptide ◽  
Peptide Component ◽  
Mutant Forms ◽  
Β Sheet ◽  
Early Onset Parkinson’S Disease ◽  
Apoptotic Mechanism

Fibrillar deposits of α-synuclein occur in several neurodegenerative diseases. Two mutant forms of α-synuclein have been associated with early-onset Parkinson's disease, and a fragment has been identified as the non-amyloid-β peptide component of Alzheimer's disease amyloid (NAC). Upon aging, solutions of α-synuclein and NAC change conformation to β-sheet, detectable by CD spectroscopy, and form oligomers that deposit as amyloid-like fibrils, detectable by electron microscopy. These aged peptides are also neurotoxic. Experiments on fragments of NAC have enabled the region of NAC responsible for its aggregation and toxicity to be identified. NAC(8–18) is the smallest fragment that aggregates, as indicated by the concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. Fragments NAC(8–18) and NAC(8–16) are toxic, whereas NAC(12–18), NAC(9–16) and NAC(8–15) are not. Hence residues 8–16 of NAC comprise the region crucial for toxicity. Toxicity induced by α-synuclein, NAC and NAC(1–18) oligomers occurs via an apoptotic mechanism, possibly initiated by oxidative damage, since these peptides liberate hydroxyl radicals in the presence of iron. Molecules with anti-aggregational and/or antioxidant properties may therefore be potential therapeutic agents.

Functions of the neuron-specific protein ADAP1 (centaurin-α1) in neuronal differentiation and neurodegenerative diseases, with an overview of structural and biochemical properties of ADAP1

2014 ◽  
Vol 395 (11) ◽  
pp. 1321-1340 ◽  
Author(s):  
Rolf Stricker ◽  
Georg Reiser
Keyword(s):  
Neuronal Differentiation ◽  
Amyloid Β ◽  
Structural Data ◽  
Specific Protein ◽  
Biochemical Properties ◽  
Scaffolding Protein ◽  
Neuronal Polarity ◽  
Amyloid Β Peptide ◽  
Ph Domain ◽  
Mitochondrial Functions

Abstract Eukaryotic cells express numerous ArfGAPs (ADP-ribosylation factor GTPase-activating proteins). There is increasing knowledge about the function of the brain-specific protein ADAP1 [ArfGAP with dual pleckstrin homology (PH) domain] as well as about its biochemical properties. The ADAP subfamily, also designated centaurin-α, has an N-terminal ArfGAP domain followed by two PH domains. The mammalian ADAP subfamily consists of two identified isoforms, ADAP1 and ADAP2 (centaurin-α1 and -α2). ADAP1 is highly expressed in neurons. We highlight the functional roles of ADAP1 in neuronal differentiation and neurodegeneration. Because of interactions with different proteins and phosphoinositol-lipids, ADAP1 can function as a scaffolding protein in several signal transduction pathways. Firstly, ADAP1 mediates cytoskeletal crosstalk. This is indicated by multiple interactions of ADAP1 with components of the actin and microtubule cytoskeleton. Secondly, regulation of neuronal polarity formation and axon specification by ADAP1 is suggested by crystal structural data obtained for human ADAP1, and the complexes of ADAP1-Ins(1,3,4,5)P4 and/or the forkhead-associated domain of the kinesin KIF13B. These structures support the concept that a KIF13B-ADAP1 complex enhances the local accumulation of PtdIns(3,4,5)P3 at the tips of neurites, and thus favors neuronal polarity. Thirdly, recent evidence unravels a pathological role of ADAP1 because upregulation of ADAP1 by amyloid β-peptide causes ADAP1-Ras-ERK-dependent translocation of Elk-1 to mitochondria. This impairs mitochondrial functions with subsequent synaptic dysfunction and exacerbates neurodegeneration, as in Alzheimer’s disease.

scholarly journals Computational Analysis of the Interactions between the S100B Extracellular Chaperone and Its Amyloid β Peptide Client

2021 ◽  
Vol 22 (7) ◽  
pp. 3629
Author(s):  
Filipe E. P. Rodrigues ◽  
António J. Figueira ◽  
Cláudio M. Gomes ◽  
Miguel Machuqueiro
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Structural Data ◽  
Md Simulations ◽  
Binding Mode ◽  
Inhibitory Effect ◽  
Amyloid Β Peptide ◽  
Coulombic Interactions ◽  
Aggregation Activity

S100B is an astrocytic extracellular Ca2+-binding protein implicated in Alzheimer’s disease, whose role as a holdase-type chaperone delaying Aβ42 aggregation and toxicity was recently uncovered. Here, we employ computational biology approaches to dissect the structural details and dynamics of the interaction between S100B and Aβ42. Driven by previous structural data, we used the Aβ25–35 segment, which recapitulates key aspects of S100B activity, as a starting guide for the analysis. We used Haddock to establish a preferred binding mode, which was studied with the full length Aβ using long (1 μs) molecular dynamics (MD) simulations to investigate the structural dynamics and obtain representative interaction complexes. From the analysis, Aβ-Lys28 emerged as a key candidate for stabilizing interactions with the S100B binding cleft, in particular involving a triad composed of Met79, Thr82 and Glu86. Binding constant calculations concluded that coulombic interactions, presumably implicating the Lys28(Aβ)/Glu86(S100B) pair, are very relevant for the holdase-type chaperone activity. To confirm this experimentally, we examined the inhibitory effect of S100B over Aβ aggregation at high ionic strength. In agreement with the computational predictions, we observed that electrostatic perturbation of the Aβ-S100B interaction decreases anti-aggregation activity. Altogether, these findings unveil features relevant in the definition of selectivity of the S100B chaperone, with implications in Alzheimer’s disease.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Insights into amyloid disease from fly models

2014 ◽  
Vol 56 ◽  
pp. 69-83 ◽  
Author(s):  
Ko-Fan Chen ◽  
Damian C. Crowther
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Disease Pathogenesis ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
Polypeptide Chains ◽  
Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

Analytical methods to explore Amyloid-β-Peptide variants beyond Aβ1-40 and Aβ1-42

2015 ◽  
Vol 48 (06) ◽  
Author(s):  
H Esselmann ◽  
C Hafermann ◽  
O Jahn ◽  
I Kraus ◽  
J Vogelgsang ◽  
...  
Keyword(s):  
Analytical Methods ◽  
Amyloid Β ◽  
Amyloid Β Peptide

Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

2018 ◽  
Vol 15 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Dominik Szwajgier ◽  
Ewa Baranowska-Wojcik ◽  
Kamila Borowiec
Keyword(s):  
Phenolic Acids ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Amyloid Β Peptide ◽  
Beneficial Effects ◽  
Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

Is it All Said for NSAIDs in Alzheimer’s Disease? Role of Mitochondrial Calcium Uptake

2018 ◽  
Vol 15 (6) ◽  
pp. 504-510 ◽  
Author(s):  
Sara Sanz-Blasco ◽  
Maria Calvo-Rodríguez ◽  
Erica Caballero ◽  
Monica Garcia-Durillo ◽  
Lucia Nunez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Amyloid Β ◽  
Epidemiological Data ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Mitochondrial Potential ◽  
Disease Modifying Drugs ◽  
Definitive Evidence

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

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