scholarly journals Surprising toxicity and assembly behaviour of amyloid β-protein oxidized to sulfone

2010 ◽  
Vol 433 (2) ◽  
pp. 323-332 ◽  
Author(s):  
Panchanan Maiti ◽  
Roberto Piacentini ◽  
Cristian Ripoli ◽  
Claudio Grassi ◽  
Gal Bitan
Keyword(s):  
Amino Acids ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Β Protein ◽  
Wild Type ◽  
Neuronal Viability ◽  
Β Protein ◽  
Aβ Amyloid ◽  
Assembly Kinetics ◽  
Ad Alzheimer’S Disease

Aβ (amyloid β-peptide) is believed to cause AD (Alzheimer's disease). Aβ42 (Aβ comprising 42 amino acids) is substantially more neurotoxic than Aβ40 (Aβ comprising 40 amino acids), and this increased toxicity correlates with the existence of unique Aβ42 oligomers. Met35 oxidation to sulfoxide or sulfone eliminates the differences in early oligomerization between Aβ40 and Aβ42. Met35 oxidation to sulfoxide has been reported to decrease Aβ assembly kinetics and neurotoxicity, whereas oxidation to sulfone has rarely been studied. Based on these data, we expected that oxidation of Aβ to sulfone would also decrease its toxicity and assembly kinetics. To test this hypothesis, we compared systematically the effect of the wild-type, sulfoxide and sulfone forms of Aβ40 and Aβ42 on neuronal viability, dendritic spine morphology and macroscopic Ca2+ currents in primary neurons, and correlated the data with assembly kinetics. Surprisingly, we found that, in contrast with Aβ-sulfoxide, Aβ-sulfone was as toxic and aggregated as fast, as wild-type Aβ. Thus, although Aβ-sulfone is similar to Aβ-sulfoxide in its dipole moment and oligomer size distribution, it behaves similarly to wild-type Aβ in its aggregation kinetics and neurotoxicity. These surprising data decouple the toxicity of oxidized Aβ from its initial oligomerization, and suggest that our current understanding of the effect of methionine oxidation in Aβ is limited.

scholarly journals A High-Throughput Screen to Identify Inhibitors of Amyloid β-Protein Precursor Processing

2005 ◽  
Vol 10 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Pancham Bakshi ◽  
Yung-Feng Liao ◽  
Jun Gao ◽  
Jake Ni ◽  
Ross Stein ◽  
...  
Keyword(s):  
High Throughput ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Β Protein ◽  
High Throughput Screen ◽  
Transcription Activator ◽  
Protein Precursor ◽  
App Processing ◽  
Chemical Structures ◽  
Β Protein

Cerebral accumulation of the amyloid β-peptide (Aβ) is believed to play a key role in the pathogenesis of Alzheimer’s disease (AD). Because Aβ is produced from the proteolysis of amyloid β-protein precursor (APP) by β-and γ-secretases, these enzymes are considered important drug targets for AD. The authors have developed a luciferase-based reporter system that can identify new molecules that inhibit APP processing in a high-throughput manner. Such molecules can help in understanding the biology of APP and APP processing and in developing new drug prototypes for AD. In this system, APP is fused on its C-terminus with Gal4-VP16, a chimeric yeast-viral transcription activator, and luciferase is under control of the yeast Gal4 promoter. Compounds that modulate the luciferase signal may affect the secretases directly, interact with modifiers of these proteases, or interact with APP directly. The authors successfully interfaced this assay with a high-throughput screen, testing ~60,000 compounds with diverse chemical structures. In principle, this sensitive, specific, and quantitative assay may be useful for identifying both inhibitors and stimulators of APP processing.( Journal of Biomolecular Screening 2005:1-12)

The proteins BACE1 and BACE2 and β-secretase activity in normal and Alzheimer's disease brain

2007 ◽  
Vol 35 (3) ◽  
pp. 574-576 ◽  
Author(s):  
J.H. Stockley ◽  
C. O'Neill
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Protein Levels ◽  
Rate Limiting Step ◽  
Secretase Activity ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease ◽  
And Function

The insidious progression of AD (Alzheimer's disease) is believed to be linked closely to the production, accumulation and aggregation of the ∼4.5 kDa protein fragment called Aβ (amyloid β-peptide). Aβ is produced by sequential cleavage of the amyloid precursor protein by two enzymes referred to as β- and γ-secretase. β-Secretase is of central importance, as it catalyses the rate-limiting step in the production of Aβ and was identified 7 years ago as BACE1 (β-site APP-cleaving enzyme 1). Soon afterwards, its homologue BACE2 was discovered, and both proteins represent a new subclass of the aspartyl protease family. Studies examining the regulation and function of β-secretase in the normal and AD brain are central to the understanding of excessive production of Aβ in AD, and in targeting and normalizing this β-secretase process if it has gone awry in the disease. Several reports indicate this, showing increased β-secretase activity in AD, with recent findings by our group showing changes in β-secretase enzyme kinetics in AD brain caused by an increased Vmax. This article gives a brief review of studies which have examined BACE1 protein levels and β-secretase activity in control and AD brain, considering further the expression of BACE2 in the human brain.

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).

Protein–protein interactions in the assembly and subcellular trafficking of the BACE (β-site amyloid precursor protein-cleaving enzyme) complex of Alzheimer's disease

2007 ◽  
Vol 35 (5) ◽  
pp. 974-979 ◽  
Author(s):  
R.B. Parsons ◽  
B.M. Austen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Protein Interactions ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

The correct assembly of the BACE (β-site amyloid precursor protein-cleaving enzyme or β-secretase) complex and its subsequent trafficking to cellular compartments where it associates with the APP (amyloid precursor protein) is essential for the production of Aβ (amyloid β-peptide), the protein whose aggregation into senile plaques is thought to be responsible for the pathogenesis of AD (Alzheimer's disease). These processes rely upon both transient and permanent BACE–protein interactions. This review will discuss what is currently known about these BACE–protein interactions and how they may reveal novel therapeutic targets for the treatment of AD.

Transcranial Laser Therapy Attenuates Amyloid-β Peptide Neuropathology in Amyloid-β Protein Precursor Transgenic Mice

2011 ◽  
Vol 23 (3) ◽  
pp. 521-535 ◽  
Author(s):  
Luis De Taboada ◽  
Jin Yu ◽  
Salim El-Amouri ◽  
Sebastiano Gattoni-Celli ◽  
Steve Richieri ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Laser Therapy ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein

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.

Novel heparan sulphate analogues: inhibition of β-secretase cleavage of amyloid precursor protein

2005 ◽  
Vol 33 (5) ◽  
pp. 1116-1118 ◽  
Author(s):  
S.J. Patey ◽  
E.A. Yates ◽  
J.E. Turnbull
Keyword(s):  
Amyloid Precursor Protein ◽  
Heparan Sulphate ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Neuritic Plaques ◽  
Rate Limiting Step ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

The role of HS (heparan sulphate) in the pathology of AD (Alzheimer's disease) is multifaceted. HS and other glycosaminoglycans have been widely reported to be associated with neuritic plaques. HS has also been shown to promote the aggregation of Aβ (amyloid β-peptide), the proteinaceous component of neuritic plaques. Recently, we described a novel and contrasting role for HS in the pathology of AD: HS can inhibit the formation of Aβ, by directly interacting with the protease BACE1 (β-site amyloid precursor protein cleaving enzyme 1; β-secretase 1), that cleaves the amyloid precursor protein and is the rate limiting step in the generation of Aβ. Here, we review the current roles of HS and the potential for HS-derivatives in the treatment of AD.

Novel mutations introduced at the β-site of amyloid β protein precursor enhance the production of amyloid β peptide by BACE1 in vitro and in cells

2005 ◽  
Vol 7 (2) ◽  
pp. 139-148 ◽  
Author(s):  
Xiao-Ping Shi ◽  
Katherine Tugusheva ◽  
James E. Bruce ◽  
Adam Lucka ◽  
Elizabeth Chen-Dodson ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Β Protein ◽  
Novel Mutations ◽  
Protein Precursor ◽  
Β Protein ◽  
In Cells

Protein lipidation of BACE

2005 ◽  
Vol 33 (5) ◽  
pp. 1091-1093 ◽  
Author(s):  
R.B. Parsons ◽  
B.M. Austen
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Protein ◽  
Lipid Modification ◽  
Β Protein ◽  
Aβ Amyloid ◽  
Protein Lipidation

Our research has concentrated upon the protein lipid modification of BACE [β-site amyloid precursor protein cleaving enzyme (β-secretase)], of which very little is currently known. Lipidation influences the production of Aβ (amyloid β-protein) by promoting the dimerization of BACE.

Modulation of tau pathology in tau transgenic models

2010 ◽  
Vol 38 (4) ◽  
pp. 996-1000 ◽  
Author(s):  
Jean-Pierre Brion ◽  
Kunie Ando ◽  
Céline Heraud ◽  
Karelle Leroy
Keyword(s):  
Neuronal Death ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Amyloid Β Peptide ◽  
Wild Type ◽  
Tau Pathology ◽  
Amyloid Pathology ◽  
Aβ Amyloid ◽  
Tau Aggregation ◽  
The Relationship

NFTs (neurofibrillary tangles) in Alzheimer's disease and in tauopathies are hallmark neuropathological lesions whose relationship with neuronal dysfunction, neuronal death and with other lesions [such as Aβ (amyloid β-peptide) pathology] are still imperfectly understood. Many transgenic mice overexpressing wild-type or mutant tau proteins have been generated to investigate the physiopathology of tauopathies. Most of the mice overexpressing wild-type tau do not develop NFTs, but can develop a severe axonopathy, whereas overexpression of mutant tau leads to NFT formation, synaptic loss and neuronal death in several models. The association between neuronal death and NFTs has, however, been challenged in some models showing a dissociation between tau aggregation and tau toxicity. Cross-breeding of mice developing NFTs with mice developing Aβ deposits increases NFT pathology, highlighting the relationship between tau and amyloid pathology. On the other hand, tau expression seems to be necessary for expression of a pathological phenotype associated with amyloid pathology. These findings suggest that there is a bilateral cross-talk between Aβ and tau pathology. These observations are discussed by the presentation of some relevant models developed recently.

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