Is Covalently Crosslinked A&amp;#946; Responsible for Synaptotoxicity in Alzheimers Disease?

Naylor, Ryan; Hill, Andrew F.; Barnham, KJ

doi:10.2174/156720508786898433

Cited by 10 publications

(8 citation statements)

References 80 publications

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“…Additionally, the examination of sAPPα as downregulated protein may be of further relevance in the differential diagnosis of meningitis, maybe reflecting pre-synaptical pathological [40] or protective processes [18] as seen in neurodegenerative diseases like AD [41], [42]. Further studies with the aim to validate the role of APP–best with robust tests for sAPPα/β–in the clinical workflow will investigate if this protein is a complementary marker in those cases where GFAP levels are not pathbraking.…”

Section: Discussionmentioning

confidence: 99%

A Proteomic Approach for the Diagnosis of Bacterial Meningitis

et al. 2010

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BackgroundThe discrimination of bacterial meningitis (BM) versus viral meningitis (VM) shapes up as a problem, when laboratory data are not equivocal, in particular, when Gram stain is negative.Methodology/Principal FindingsWith the aim to determine reliable marker for bacterial or viral meningitis, we subjected cerebrospinal fluid (CSF) to a quantitative proteomic screening. By using a recently established 2D-DIGE protocol which was adapted to the individual CSF flow, we compared a small set of patients with proven BM and VM. Thereby, we identified six potential biomarkers out of which Prostaglandin-H2 D-isomerase was already described in BM, showing proof of concept. In the subsequent validation phase on a more comprehensive collective of 80 patients, we could validate that in BM high levels of glial fibrillary acidic protein (GFAP) and low levels of soluble amyloid precursor protein alpha/beta (sAPPα/β) are present as possible binding partner of Fibulin-1.Conclusions/SignificanceWe conclude that our CSF flow-adapted 2D-DIGE protocol is valid especially in comparing samples with high differences in total protein and suppose that GFAP and sAPPα/β have a high potential as additional diagnostic markers for differentiation of BM from VM. In the clinical setting, this might lead to an improved early diagnosis and to an individual therapy.

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Section: Discussionmentioning

confidence: 99%

A Proteomic Approach for the Diagnosis of Bacterial Meningitis

et al. 2010

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“…The soluble oligomers obtained from the culturing of cells possess high chemical resistance and protect against its conversion into monomers via several degrading factors and maintain the presence of covalent cross-links in them [ 134 , 135 ]. Binding of Cu 2+ ions increases dityrosine-linked β-amyloid dimers as observed in vitro studies of this neurological disorder [ 136 , 137 , 138 , 139 ].…”

Section: Copper Ion Implication In Admentioning

confidence: 99%

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Ejaz

Wang

Lang

2020

IJMS

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Alzheimer’s disease (AD) is an irreversible, age-related progressive neurological disorder, and the most common type of dementia in aged people. Neuropathological lesions of AD are neurofibrillary tangles (NFTs), and senile plaques comprise the accumulated amyloid-beta (Aβ), loaded with metal ions including Cu, Fe, or Zn. Some reports have identified metal dyshomeostasis as a neurotoxic factor of AD, among which Cu ions seem to be a central cationic metal in the formation of plaque and soluble oligomers, and have an essential role in the AD pathology. Cu-Aβ complex catalyzes the generation of reactive oxygen species (ROS) and results in oxidative damage. Several studies have indicated that oxidative stress plays a crucial role in the pathogenesis of AD. The connection of copper levels in AD is still ambiguous, as some researches indicate a Cu deficiency, while others show its higher content in AD, and therefore there is a need to increase and decrease its levels in animal models, respectively, to study which one is the cause. For more than twenty years, many in vitro studies have been devoted to identifying metals’ roles in Aβ accumulation, oxidative damage, and neurotoxicity. Towards the end, a short review of the modern therapeutic approach in chelation therapy, with the main focus on Cu ions, is discussed. Despite the lack of strong proofs of clinical advantage so far, the conjecture that using a therapeutic metal chelator is an effective strategy for AD remains popular. However, some recent reports of genetic-regulating copper transporters in AD models have shed light on treating this refractory disease. This review aims to succinctly present a better understanding of Cu ions’ current status in several AD features, and some conflicting reports are present herein.

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“…Moreover, some studies show that senile plaques exist in cognitively normal people ( Jack et al, 2010 ; Sperling et al, 2011 ; Swerdlow, 2011 ; Esparza et al, 2013 ) and, despite an equivalent plaque presence, the concentration of brain amyloid oligomers is higher in AD patients than in normal cases. The “Toxic oligomers hypothesis” explains these events by suggesting that small, diffusible oligomers are responsible for toxicity, and not the amyloid plaques ( Naylor et al, 2008 ; Sarell, 2010 ). The oligomers derived from cell culture have unusually high chemical stability and resist degradation into monomers by various degrading agents, supporting the existence of covalent cross-links between the oligomers ( Podlisny et al, 1995 ; Walsh et al, 2002 ; Lesné et al, 2006 ; Naylor et al, 2008 ).…”

Section: Copper Ion Toxicity In Admentioning

confidence: 99%

Role of Copper in the Onset of Alzheimer’s Disease Compared to Other Metals

Bagheri

Squitti

Haertlé

et al. 2018

Front. Aging Neurosci.

173

121

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Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by amyloid plaques in patients’ brain tissue. The plaques are mainly made of β-amyloid peptides and trace elements including Zn2+, Cu2+, and Fe2+. Some studies have shown that AD can be considered a type of metal dyshomeostasis. Among metal ions involved in plaques, numerous studies have focused on copper ions, which seem to be one of the main cationic elements in plaque formation. The involvement of copper in AD is controversial, as some studies show a copper deficiency in AD, and consequently a need to enhance copper levels, while other data point to copper overload and therefore a need to reduce copper levels. In this paper, the role of copper ions in AD and some contradictory reports are reviewed and discussed.

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Is Covalently Crosslinked Aβ Responsible for Synaptotoxicity in Alzheimers Disease?

Cited by 10 publications

References 80 publications

A Proteomic Approach for the Diagnosis of Bacterial Meningitis

A Proteomic Approach for the Diagnosis of Bacterial Meningitis

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

Role of Copper in the Onset of Alzheimer’s Disease Compared to Other Metals

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