The p3 Peptide, a Naturally Occurring Fragment of the Amyloid-β Peptide (Aβ)Found in Alzheimer's Disease, Has a Greater Aggregation Propensity In Vitro Than Full-Length Aβ, But Does Not Bind Cu2+.

2000 ◽  
Vol 53 (4) ◽  
pp. 321 ◽  
Author(s):  
Feda Ali ◽  
Andrew J. Thompson ◽  
Colin J. Barrow
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down's Syndrome ◽  
Amyloid Β ◽  
Down’S Syndrome ◽  
Full Length ◽  
Amyloid Β Peptide ◽  
Sheet Structure ◽  
Β Sheet

Cerebellar preamyloid from both Down’s syndrome and Alzheimer’s disease contains the p3 fragment (Aβ 17–40/42) as a major amyloid-β peptide (Aβ) component. The p3 peptide was previously shown to form amyloid in vitro, but less readily than full-length Aβ. Here we show that the p3 peptide has a greater β-sheet-forming propensity than full-length Aβ. Using circular dichroism spectroscopy we determined that in aqueous solutions the p3 peptide forms β-sheet structure more readily than full-length Aβ. The p3 peptide also has a lower α-helical propensity than full-length Aβ in the structure-forming solvent trifluoroethanol. These results indicate that the lower amyloidogenicity of the p3 peptide is not related to an inability to form β-sheet structure. In this study we also show that, unlike full-length Aβ, the p3 peptide does not bind Cu2+ ions. This inability to bind copper ions may explain why the p3 peptide appears to play a lesser role in Down’s syndrome and Alzheimer’s disease related neurodegeneration than does full-length Aβ.

scholarly journals Heterogeneity of water-soluble amyloid β-peptide in Alzheimer's disease and Down's syndrome brains

FEBS Letters ◽  
1997 ◽  
Vol 409 (3) ◽  
pp. 411-416 ◽  
Author(s):  
Claudio Russo ◽  
Takaomi C. Saido ◽  
Laura M. DeBusk ◽  
Massimo Tabaton ◽  
Pierluigi Gambetti ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down's Syndrome ◽  
Amyloid Β ◽  
Down’S Syndrome ◽  
Water Soluble ◽  
Amyloid Β Peptide

scholarly journals The molecular biology of Alzheimer's disease

1991 ◽  
Vol 15 (9) ◽  
pp. 564-565
Author(s):  
L. J. Whalley
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acids ◽  
Gene Dosage ◽  
Down's Syndrome ◽  
Amyloid Β ◽  
Down’S Syndrome ◽  
Mental Illnesses ◽  
Amyloid Β Protein ◽  
Β Protein

For some years, the pace of progress in clinical neuroscience has progressively quickened but none more so than with molecular biological techniques. Clinical psychiatrists have been promised (some say forewarned) that the systematic application of these techniques will swiftly cut through the multifactorial aetiologies of many mental illnesses and revolutionise diagnosis, treatment and, possibly prevention. Not surprisingly, given the fact that Down's syndrome and Alzheimer's neuropathological changes (senile plaques and neurofibrillary tangles) are so tightly linked, understanding of Alzheimer's disease (AD) was the first mental illness to benefit from these new methods. Once the amyloid β protein component of the senile plaque had been isolated and its 39–43 constituent amino acids sequenced, then it became almost a routine matter to locate the gene and describe comprehensively the much larger (approximately 710 amino acids) amyloid β protein precursor (APP). Almost simultaneously, the gene responsible for familial pre-senile Alzheimer's disease (FAD) was located, like the APP gene, on chromosome 21 (Tanzi et al, 1989). Soon, a claim was made that these (FAD and APP) were the same gene, and, in a manner akin to the presumed causal gene dosage effects in Down's syndrome, Alzheimer's disease was attributed to excess production of amyloid (by way of APP). However, this was quickly refuted and data to support a gene dosage effect in AD were not confirmed. The trail then seemed to go cold. Several studies indicated that FAD was genetically heterogeneous and distinct from senile AD (St George-Hyslop et al, 1990), and the problems of prion disease in animals and man secured more attention (Westaway et al, 1989).

Phosphorylation of a full length amyloid-β peptide modulates its amyloid aggregation, cell binding and neurotoxic properties

2017 ◽  
Vol 13 (8) ◽  
pp. 1545-1551 ◽  
Author(s):  
Elaheh Jamasbi ◽  
Frances Separovic ◽  
Mohammed Akhter Hossain ◽  
Giuseppe Donato Ciccotosto
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Full Length ◽  
Amyloid Β Peptide ◽  
Amyloid Aggregation ◽  
Cell Binding ◽  
The Brain

Phosphorylation of Aβ42 promotes the formation of amyloid plaques in the brain, which lack the neurotoxic properties associated with oligomeric species causing pathogenesis in Alzheimer's disease.

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.

Inhibition of Aβ(1–40) fibril formation by cyclophilins

2016 ◽  
Vol 473 (10) ◽  
pp. 1355-1368 ◽  
Author(s):  
Marten Villmow ◽  
Monika Baumann ◽  
Miroslav Malesevic ◽  
Rolf Sachs ◽  
Gerd Hause ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Water Soluble ◽  
Main Process ◽  
Amyloid Β Peptide ◽  
Cyclophilin D ◽  
Aβ Amyloid

Cyclophilins interact directly with the Alzheimer's disease peptide Aβ (amyloid β-peptide) and are therefore involved in the early stages of Alzheimer's disease. Aβ binding to CypD (cyclophilin D) induces dysfunction of human mitochondria. We found that both CypD and CypA suppress in vitro fibril formation of Aβ(1–40) at substoichiometric concentrations when present early in the aggregation process. The prototypic inhibitor CsA (cyclosporin A) of both cyclophilins as well as the new water-soluble MM258 derivative prevented this suppression. A SPOT peptide array approach and NMR titration experiments confirmed binding of Aβ(1–40) to the catalytic site of CypD mainly via residues Lys16–Glu22. The peptide Aβ(16–20) representing this section showed submicromolar IC50 values for the peptidyl prolyl cis–trans isomerase activity of CypD and CypA and low-micromolar KD values in ITC experiments. Chemical cross-linking and NMR-detected hydrogen–deuterium exchange experiments revealed a shift in the populations of small Aβ(1–40) oligomers towards the monomeric species, which we investigated in the present study as being the main process of prevention of Aβ fibril formation by cyclophilins.

scholarly journals α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease

2019 ◽  
Vol 116 (18) ◽  
pp. 8895-8900 ◽  
Author(s):  
Dylan Shea ◽  
Cheng-Chieh Hsu ◽  
Timothy M. Bi ◽  
Natasha Paranjapye ◽  
Matthew Carter Childers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Secondary Structure ◽  
De Novo ◽  
Specific Binding ◽  
Amyloid Β ◽  
Plaque Burden ◽  
Lag Phase ◽  
Amyloid Β Peptide ◽  
Β Sheet

Alzheimer’s disease (AD) is characterized by the deposition of β-sheet–rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed “α-sheet.” These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

scholarly journals Assembling amyloid fibrils from designed structures containing a significant amyloid β-peptide fragment

2002 ◽  
Vol 366 (1) ◽  
pp. 343-351 ◽  
Author(s):  
Lars O. TJERNBERG ◽  
Agneta TJERNBERG ◽  
Niklas BARK ◽  
Yuan SHI ◽  
Bela P. RUZSICSKA ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Structural Features ◽  
Fibril Formation ◽  
Amyloid Β Peptide ◽  
Detailed Model ◽  
Aβ Fibrils ◽  
Β Sheet

The amyloid plaque, consisting of amyloid β-peptide (Aβ) fibrils surrounded by dystrophic neurites, is an invariable feature of Alzheimer's disease. The determination of the molecular structure of Aβ fibrils is a significant goal that may lead to the structure-based design of effective therapeutics for Alzheimer's disease. Technical challenges have thus far rendered this goal impossible. In the present study, we develop an alternative methodology. Rather than determining the structure directly, we design conformationally constrained peptides and demonstrate that only certain ‘bricks’ can aggregate into fibrils morphologically identical to Aβ fibrils. The designed peptides include variants of a decapeptide fragment of Aβ, previously shown to be one of the smallest peptides that (1) includes a pentapeptide sequence necessary for Aβ—Aβ binding and aggregation and (2) can form fibrils indistinguishable from those formed by full-length Aβ. The secondary structure of these bricks is monitored by CD spectroscopy, and electron microscopy is used to study the morphology of the aggregates formed. We then made various residue deletions and substitutions to determine which structural features are essential for fibril formation. From the constraints, statistical analysis of side-chain pair correlations in β-sheets and experimental data, we deduce a detailed model of the peptide strand alignment in fibrils formed by these bricks. Our results show that the constrained decapeptide dimers rapidly form an intramolecular, antiparallel β-sheet and polymerize into amyloid fibrils at low concentrations. We suggest that the formation of an exposed β-sheet (e.g. an Aβ dimer formed by interaction in the decapeptide region) could be a rate-limiting step in fibril formation. A theoretical framework that explains the results is presented in parallel with the data.

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