Nuclear tau and its potential role in Alzheimer’s disease

Tau protein, found in both neuronal and non-neuronal cells, forms aggregates in neurons that constitutes one of the hallmarks of Alzheimer’s disease (AD). For nearly four decades, research efforts have focused more on tau’s role in physiology and pathology in the context of the microtubules, even though, for over three decades, tau has been localised in the nucleus and the nucleolus. Its nuclear and nucleolar localisation had stimulated many questions regarding its role in these compartments. Data from cell culture, mouse brain, and the human brain suggests that nuclear tau could be essential for genome defense against cellular distress. However, its nature of translocation to the nucleus, its nuclear conformation and interaction with the DNA and other nuclear proteins highly suggest it could play multiple roles in the nucleus. To find efficient tau-based therapies, there is a need to understand more about the functional relevance of the varied cellular distribution of tau, identify whether specific tau transcripts or isoforms could predict tau’s localisation and function and how they are altered in diseases like AD. Here, we explore the cellular distribution of tau, its nuclear localisation and function and its possible involvement in neurodegeneration

Accounting Treatment of Drilling and Development Expenses Between the International Reporting Standard Ifrs 6 and the Unified Accounting System (A Comparative Study)

Purpose: The purpose of this research is to identify the accounting treatments for drilling and development expenses in the Iraqi oil companies according to the unified accounting system, and to indicate the extent of compatibility and difference in the treatment of drilling and development expenses between the unified accounting system and the International Financial Reporting Standard IFRS 6.   Theoretical framework: The oil industry includes many activities and operations, starting from research and exploration operations through drilling and development operations, and ending with extracting oil from the well and delivering it to the consumer or transferring it to the refining industry. During these activities expenses are realized that should be accounted for in a way that ensures compliance with international standards for the oil industry as Iraq particularly witness a great development in the oil industry represented in dealing with foreign oil investment companies which means the need to standardize accounting treatments for the oil industry between local oil companies and foreign oil companies.   Design/methodology/approach: The research used comparative descriptive approach by comparing the accounting treatment of drilling and development expenses under the International Financial Reporting Standard IFRS 6 and the unified accounting system applied in Iraq represented by the Basra Oil Company and the Iraqi Drilling Company.   Findings:  One of the most important findings of the research is the concord of the method used by the Basra Oil Company in capitalizing drilling expenses at the expense of wells under operation with the philosophy of the total cost method approved by the standard. However, this agreement is conditional on the absence of dry wells. If the drilling operations resulted in the presence of non-productive or productive wells but in uneconomical quantities, the treatment becomes not compatible with the standard.   The practical and social implications: The Basra Oil Company treats all development (maintenance) expenses as operating expenses that are closed at the end of the year in the income statement, this it is not consistent with the philosophy of Standard No. 6 which states that development expenses that aim to maintain the production capacity of the well should be treated as operating expenses, but if development expenses that aim to increase the production capacity of the well must be capitalized on the cost of the well.   Originality/ Value: The importance of the research comes from the need to work on applying the requirements of the International Financial Reporting Standard IFRS 6 in accounting treatments for oil expenditures, including drilling and development expenses in Iraqi oil companies

Chemical and biochemical studies of dityrosine cross-link formation in amyloidogenic peptides

Amyloid fibrils are associated with a large number of diseases in which proteins and peptides abnormally assemble to form insoluble amyloid that deposit in the tissues. However, oxidative stress has been implicated in the pathogenesis of a number of neurodegenerative diseases and is believed to play an important role in the amyloid deposition through protein cross-linkings. Under oxidative stress conditions, tyrosyl radicals can be formed and coupled to form dityrosine cross-linkage. The formation of dityrosine cross-linked oligomers is one of the oxidative modifications that may mediate the toxicity of amyloid β (Aβ) and α-synuclein (α-syn) in Alzheimer’s disease (AD) and Parkinson’s disease (PD) respectively. In this thesis, I explored the oxidative modification of two short peptides, HYFNIF and VIYKI, using a Cu2+/H2O2 oxidation system, and studied the morphological and conformational changes of these amyloid fibrils during the oxidation process. These peptides were selected as simple amyloid model systems that have been previously structurally characterised, to better understand the dityrosine formation at a structural level and to optimise the oxidation conditions. Oxidative stress has been implicated in AD. Here, I have explored the formation of dityrosine cross-linked Aβ42 in vitro. We have shown that dityrosine is generated in internalised Aβ in cell cultures. Results also revealed the prevalence of dityrosine crosslinks in amyloid plaques in brain tissue and cerebrospinal fluid from AD patients, indicating that dityrosine could be used as a biomarker of oxidative stress in AD. The ability of the Cu2+ ion to promote the formation of in vitro dityrosine cross-linked α-syn was also explored and the effect on α-syn fibrillogenesis and conformation induced by Cu2+ was investigated. The results revealed the possibility of involvement the dityrosine cross-linked α-syn dimer as a nucleus to initiate the polymerisation process of α-syn to form amyloid fibrils. Dityrosine cross-linkages can be generated in vitro using oxidation system of Cu2+/H2O2, and might play an important role in the solubility and assembly of amyloidogenic peptides and proteins that are associated in the pathogenesis of many neurodegenerative disease including AD and PD. Dityrosine cross-linkages can lend a further stability to the already stable amyloid fibrils, and this may explain their protease resistance. Dityrosine cross-links formation represents one of the possible pathways by which oligomers can be formed. Dityrosine cross-linked oligomers represent a good bio-index of oxidatively coupled tyrosine-contained proteins due to their high stability

The molecular basis for apolipoprotein E4 as the major risk factor for late onset Alzheimer's disease

Apolipoprotein E4 (ApoE4) is one of three (E2, E3 and E4) human isoforms of an -helical, 299-amino acid protein. Homozygosity for the ε4 allele is the major risk factor for developing late onset Alzheimer’s disease (AD). ApoE2, ApoE3 and ApoE4 differ at amino acid positions 112 and 158 and these sequence variations may confer conformational differences that underlie their participation in the risk of developing AD. Here, we compared the shape, oligomerisation state, conformation and stability of ApoE isoforms using a range of complementary biophysical methods including small angle X-ray scattering, analytical ultracentrifugation, circular dichroism, X-ray fibre diffraction and transmission electron microscopy We provide an in-depth and definitive study demonstrating that all three proteins are similar in stability and conformation. However, we show that ApoE4 has a propensity to polymerise to form wavy filaments which do not share the characteristics of cross- amyloid fibrils. Moreover, we provide evidence for the inhibition of ApoE4 fibril formation by ApoE3. This study shows that recombinant ApoE isoforms show no significant differences at the structural or conformational level. However, self-assembly of the ApoE4 isoform may play a role in pathogenesis and these results open opportunities for uncovering new triggers for AD onset

Oxidative Stress Conditions Result in Trapping of PHF-Core Tau (297–391) Intermediates

Funding: This work was supported by funding from Alzheimer’s Society [345 (AS-PG-16b-010)] awarded to L.C.S. and funding M.B.M. Y.K.A.-H. is supported by WisTa Laboratories Ltd. (PAR1596). The work was supported by ARUK South Coast Network. G.B. was supported by European Molecular Biology Organisation (EMBO) Short-Term Fellowship award (EMBO-STF 7674). LCS is supported by BBSRC [BB/S003657/1]. Acknowledgments: TEM work was performed at the University of Sussex’s Electron microscopy imaging centre (EMC), funded by the School of Life Sciences, the Wellcome Trust (095605/Z/11/A, 208348/Z/17/Z) and the RM Phillips Trust. The authors thank Pascale Schellenberger for valuable support.Peer reviewedPublisher PD

The involvement of dityrosine crosslinking in α-synuclein assembly and deposition in Lewy Bodies in Parkinson’s disease

Parkinson’s disease (PD) is characterized by intracellular, insoluble Lewy bodies composed of highly stable α-synuclein (α-syn) amyloid fibrils. α-synuclein is an intrinsically disordered protein that has the capacity to assemble to form β-sheet rich fibrils. Oxidiative stress and metal rich environments have been implicated in triggering assembly. Here, we have explored the composition of Lewy bodies in post-mortem tissue using electron microscopy and immunogold labeling and revealed dityrosine crosslinks in Lewy bodies in brain tissue from PD patients. In vitro, we show that dityrosine cross-links in α-syn are formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress by fluorescence and confirmed using mass-spectrometry. A covalently cross-linked dimer isolated by SDS-PAGE and mass analysis showed that dityrosine dimer was formed via the coupling of Y39-Y39 to give a homo dimer peptide that may play a key role in formation of oligomeric and seeds for fibril formation. Atomic force microscopy analysis reveals that the covalent dityrosine contributes to the stabilization of α-syn assemblies. Thus, the presence of oxidative stress induced dityrosine could play an important role in assembly and toxicity of α-syn in PD

A central role for dityrosine crosslinking of Amyloid-β in Alzheimer’s disease

Background Alzheimer’s disease (AD) is characterized by the deposition of insoluble amyloid plaques in the neuropil composed of highly stable, self-assembled Amyloid-beta (Aβ) fibrils. Copper has been implicated to play a role in Alzheimer’s disease. Dimers of Aβ have been isolated from AD brain and have been shown to be neurotoxic. Results We have investigated the formation of dityrosine cross-links in Aβ42 formed by covalent ortho-ortho coupling of two tyrosine residues under conditions of oxidative stress with elevated copper and shown that dityrosine can be formed in vitro in Aβ oligomers and fibrils and that these links further stabilize the fibrils. Dityrosine crosslinking was present in internalized Aβ in cell cultures treated with oligomeric Aβ42 using a specific antibody for dityrosine by immunogold labeling transmission electron microscopy. Results also revealed the prevalence of dityrosine crosslinks in amyloid plaques in brain tissue and in cerebrospinal fluid from AD patients. Conclusions Aβ dimers may be stabilized by dityrosine crosslinking. These results indicate that dityrosine cross-links may play an important role in the pathogenesis of Alzheimer’s disease and can be generated by reactive oxygen species catalyzed by Cu2+ ions. The observation of increased Aβ and dityrosine in CSF from AD patients suggests that this could be used as a potential biomarker of oxidative stress in AD