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Article ; Online: Platelet Membrane β-Secretase Activity in Mild Cognitive Impairment and Conversion to Dementia: a Longitudinal Study.

McGuinness, Bernadette / Fuchs, Marc / Barrett, Suzanne L / Passmore, A Peter / Johnston, Janet A

2016 Volume 49, Issue 4, Page(s) 1095–1103

Abstract: A blood-based biomarker to complement the clinical and neuropsychological assessments used to evaluate the risk of individuals with mild cognitive impairment (MCI) developing Alzheimer's disease (AD) would be invaluable. Previous pilot studies by our ... ...

Abstract	A blood-based biomarker to complement the clinical and neuropsychological assessments used to evaluate the risk of individuals with mild cognitive impairment (MCI) developing Alzheimer's disease (AD) would be invaluable. Previous pilot studies by our group identified elevated platelet membrane β-secretase activity in patients with AD and MCI, as compared to controls, and this activity was influenced by membrane cholesterol levels. The present study investigated baseline platelet membrane β-secretase activity and cholesterol levels in 97 MCI participants and 85 controls and explored whether these parameters differed in individuals with stable MCI, as compared to those who subsequently developed AD. To evaluate signal specificity, β-secretase activity assays were conducted in the presence and absence of beta-site amyloid-β protein precursor-cleaving enzyme (BACE) inhibitors. Baseline platelet membrane β-secretase activity did not differ significantly in MCI participants, as compared to controls, and platelet membrane cholesterol levels were significantly lower in the MCI group. The longitudinal study indicated that the activities inhibited by two different BACE inhibitors did not predict conversion to AD; however, the activity that was not affected by BACE inhibitors was significantly (40%) higher in individuals with stable MCI, as compared with those who subsequently developed AD. These findings indicated that further research into the source of this activity could contribute to a measure facilitating prediction of the risk of conversion from MCI to AD.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/physiopathology ; Amyloid Precursor Protein Secretases/blood ; Biomarkers/blood ; Blood Platelets/enzymology ; Cholesterol/blood ; Cognitive Dysfunction/physiopathology ; Cross-Sectional Studies ; Disease Progression ; Female ; Follow-Up Studies ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Neuropsychological Tests ; Sensitivity and Specificity
Chemical Substances	Biomarkers ; Cholesterol (97C5T2UQ7J) ; Amyloid Precursor Protein Secretases (EC 3.4.-)
Language	English
Publishing date	2016
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-150795
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Article ; Online: The development of effective biomarkers for Alzheimer's disease: a review.

Henry, Mark S / Passmore, Anthony P / Todd, Stephen / McGuinness, Bernadette / Craig, David / Johnston, Janet A

International journal of geriatric psychiatry

2013 Volume 28, Issue 4, Page(s) 331–340

Abstract: Objective: There is a widely recognised need to develop effective Alzheimer's disease (AD) biomarkers to aid the development of disease-modifying treatments, to facilitate early diagnosis and to improve clinical care. This overview aims to summarise the ...

Abstract	Objective: There is a widely recognised need to develop effective Alzheimer's disease (AD) biomarkers to aid the development of disease-modifying treatments, to facilitate early diagnosis and to improve clinical care. This overview aims to summarise the utility of key neuroimaging and cerebrospinal fluid (CSF) biomarkers for AD, before focusing on the latest efforts to identify informative blood biomarkers. Design: A literature search was performed using PubMed up to September 2011 for reviews and primary research studies of neuroimaging (magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and amyloid imaging), CSF and blood-based (plasma, serum and platelet) biomarkers in AD and mild cognitive impairment. Citations within individual articles were examined to identify additional studies relevant to this review. Results: Evidence of AD biomarker potential was available for imaging techniques reflecting amyloid burden and neurodegeneration. Several CSF measures are promising, including 42 amino acid β-amyloid peptide (Aβ42 ); total tau (T-tau) protein, reflecting axonal damage; and phosphorylated tau (P-tau), reflecting neurofibrillary tangle pathology. Studies of plasma Aβ have produced inferior diagnostic discrimination. Alternative plasma and platelet measures are described, which represent potential avenues for future research. Conclusions: Several imaging and CSF markers demonstrate utility in predicting AD progression and determining aetiology. These require standardisation before forming core elements of diagnostic criteria. The enormous potential available for identifying a minimally-invasive, easily-accessible blood measure as an effective AD biomarker currently remains unfulfilled.
MeSH term(s)	Alzheimer Disease/cerebrospinal fluid ; Alzheimer Disease/diagnosis ; Alzheimer Disease/pathology ; Biomarkers/cerebrospinal fluid ; Early Diagnosis ; Humans ; Magnetic Resonance Imaging/methods
Chemical Substances	Biomarkers
Language	English
Publishing date	2013-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	806736-3
ISSN	1099-1166 ; 0885-6230
ISSN (online)	1099-1166
ISSN	0885-6230
DOI	10.1002/gps.3829
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Article ; Online: α-Synuclein mRNA and soluble α-synuclein protein levels in post-mortem brain from patients with Parkinson's disease, dementia with Lewy bodies, and Alzheimer's disease.

Quinn, Joseph G / Coulson, David T R / Brockbank, Simon / Beyer, Nancy / Ravid, Rivka / Hellemans, Jan / Irvine, G Brent / Johnston, Janet A

Brain research

2012 Volume 1459, Page(s) 71–80

Abstract: α-Synuclein is a neuronal protein implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Whilst increased α-synuclein expression due to gene duplication or triplication can cause familial PD, previous studies of α- ... ...

Abstract	α-Synuclein is a neuronal protein implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Whilst increased α-synuclein expression due to gene duplication or triplication can cause familial PD, previous studies of α-synuclein levels in idiopathic disease have produced conflicting data. We quantified α-synuclein mRNA and soluble protein in five human post-mortem brain regions from four groups of individuals with PD, DLB, Alzheimer's disease (AD) and matched controls. α-Synuclein mRNA levels, measured using quantitative real-time PCR, did not differ significantly between groups in any brain regions examined. In contrast, levels of soluble α-synuclein protein, measured by ELISA, were significantly lower in 4 of the 5 regions for patients with DLB, and in 2 of the 5 regions for patients with PD, compared to controls. Soluble α-synuclein protein levels were not significantly different in the AD patients, compared to controls, in 4 of the 5 regions. This study indicates that although levels of soluble α-synuclein protein are lower in DLB and PD, there is no evidence for a corresponding decrease in α-synuclein mRNA levels. This might result from altered translation, or removal of α-synuclein protein from a soluble detectable state, either by turnover or conversion to an insoluble form.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/pathology ; Brain/metabolism ; Brain/pathology ; Enzyme-Linked Immunosorbent Assay ; Female ; Gene Expression Regulation/physiology ; Humans ; Lewy Body Disease/pathology ; Male ; Parkinson Disease/pathology ; Postmortem Changes ; RNA, Messenger/metabolism ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism
Chemical Substances	RNA, Messenger ; alpha-Synuclein
Language	English
Publishing date	2012-06-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2012.04.018
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Article ; Online: Zinc transporter mRNA levels in Alzheimer's disease postmortem brain.

Beyer, Nancy / Coulson, David T R / Heggarty, Shirley / Ravid, Rivka / Hellemans, Jan / Irvine, G Brent / Johnston, Janet A

Journal of Alzheimer's disease : JAD

2012 Volume 29, Issue 4, Page(s) 863–873

Abstract: Zinc (Zn2+) is concentrated into pre-synaptic vesicles and co-released with neurotransmitter at some synapses. Zn2+ can accelerate assembly of the amyloid-β peptides (Aβ) and tau protein central to the neuropathological changes found in Alzheimer's ... ...

Abstract	Zinc (Zn2+) is concentrated into pre-synaptic vesicles and co-released with neurotransmitter at some synapses. Zn2+ can accelerate assembly of the amyloid-β peptides (Aβ) and tau protein central to the neuropathological changes found in Alzheimer's disease (AD). Altered protein levels of the membrane Zn2+ transporters ZnT1, ZnT4, and ZnT6 have been reported in AD postmortem brain tissue. The present study analyzed mRNA levels of five established (LIV1, ZIP1, ZnT1, ZnT4, and ZnT6) and one potential (PRNP) Zn2+ transporter in human postmortem brain tissue from Braak-staged individuals with AD and controls using quantitative real-time PCR. Four cortical regions (middle temporal gyrus, superior occipital gyrus, superior parietal gyrus, and superior frontal gyrus) and cerebellum were examined. PRNP mRNA levels were decreased by ∼30% in all four cortical regions examined in AD patients, but unchanged in the cerebellum. In contrast, some increases in mRNA levels of the other more established Zn2+ transporters (LIV1, ZIP1, ZnT1, ZnT6) were found in AD cortex. The ratios of the mRNA levels of LIV1, ZIP1, ZnT1, ZnT4, and ZnT6/mRNA level of neuron specific enolase increased significantly as the disease progressed and Braak stage increased. Significant correlations were also identified between mRNA levels of several of the Zn2+ transporters investigated. These expression changes could either reflect or cause the altered cortical Zn2+ distribution in AD, potentially increasing the likelihood of interactions between Zn2+ and Aβ or tau protein.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/pathology ; Analysis of Variance ; Brain/metabolism ; Brain/pathology ; Carrier Proteins/classification ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Case-Control Studies ; Cation Transport Proteins/genetics ; Cation Transport Proteins/metabolism ; Female ; Glial Fibrillary Acidic Protein/genetics ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Male ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Phosphopyruvate Hydratase/genetics ; Phosphopyruvate Hydratase/metabolism ; Postmortem Changes ; RNA, Messenger/metabolism ; Statistics as Topic ; Statistics, Nonparametric
Chemical Substances	Carrier Proteins ; Cation Transport Proteins ; Glial Fibrillary Acidic Protein ; Neoplasm Proteins ; RNA, Messenger ; SLC30A1 protein, human ; SLC30A4 protein, human ; SLC30A6 protein, human ; SLC39A1 protein, human ; SLC39A6 protein, human ; zinc-binding protein ; Phosphopyruvate Hydratase (EC 4.2.1.11)
Language	English
Publishing date	2012
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-2012-112105
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Article ; Online: ZnT3 mRNA levels are reduced in Alzheimer's disease post-mortem brain

Irvine G Brent / Ravid Rivka / Heggarty Shirley / Coulson David TR / Beyer Nancy / Hellemans Jan / Johnston Janet A

Molecular Neurodegeneration, Vol 4, Iss 1, p

2009 Volume 53

Abstract: Abstract Background ZnT3 is a membrane Zn 2+ transporter that is responsible for concentrating Zn 2+ into neuronal presynaptic vesicles. Zn 2+ homeostasis in the brain is relevant to Alzheimer's disease (AD) because Zn 2+ released during ... ...

Abstract	Abstract Background ZnT3 is a membrane Zn 2+ transporter that is responsible for concentrating Zn 2+ into neuronal presynaptic vesicles. Zn 2+ homeostasis in the brain is relevant to Alzheimer's disease (AD) because Zn 2+ released during neurotransmission may bind to Aβ peptides, accelerating the assembly of Aβ into oligomers which have been shown to impair synaptic function. Results We quantified ZnT3 mRNA levels in Braak-staged human post mortem (pm) brain tissue from medial temporal gyrus, superior occipital gyrus, superior parietal gyrus, superior frontal gyrus and cerebellum from individuals with AD (n = 28), and matched controls (n = 5) using quantitative real-time PCR. ZnT3 mRNA levels were significantly decreased in all four cortical regions examined in the AD patients, to 45-60% of control levels. This reduction was already apparent at Braak stage 4 in most cortical regions examined. Quantification of neuronal and glial-specific markers in the same samples (neuron-specific enolase, NSE; and glial fibrillary acidic protein, GFAP) indicated that loss of cortical ZnT3 expression was more pronounced, and occurred prior to, significant loss of NSE expression in the tissue. Significant increases in cortical GFAP expression were apparent as the disease progressed. No gene expression changes were observed in the cerebellum, which is relatively spared of AD neuropathology. Conclusions This first study to quantify ZnT3 mRNA levels in human pm brain tissue from individuals with AD and controls has revealed a significant loss of ZnT3 expression in cortical regions, suggesting that neuronal cells in particular show reduced expression of ZnT3 mRNA in the disease. This suggests that altered neuronal Zn 2+ handling may be an early event in AD pathogenesis.
Keywords	Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	333
Language	English
Publishing date	2009-12-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: α-Synuclein mRNA and soluble α-synuclein protein levels in post-mortem brain from patients with Parkinson's disease, dementia with Lewy bodies, and Alzheimer's disease

Quinn, Joseph G / Coulson, David T.R / Brockbank, Simon / Beyer, Nancy / Ravid, Rivka / Hellemans, Jan / Irvine, G. Brent / Johnston, Janet A

Brain research. 2012 June 12, v. 1459

2012

Abstract	α-Synuclein is a neuronal protein implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Whilst increased α-synuclein expression due to gene duplication or triplication can cause familial PD, previous studies of α-synuclein levels in idiopathic disease have produced conflicting data. We quantified α-synuclein mRNA and soluble protein in five human post-mortem brain regions from four groups of individuals with PD, DLB, Alzheimer's disease (AD) and matched controls. α-Synuclein mRNA levels, measured using quantitative real-time PCR, did not differ significantly between groups in any brain regions examined. In contrast, levels of soluble α-synuclein protein, measured by ELISA, were significantly lower in 4 of the 5 regions for patients with DLB, and in 2 of the 5 regions for patients with PD, compared to controls. Soluble α-synuclein protein levels were not significantly different in the AD patients, compared to controls, in 4 of the 5 regions. This study indicates that although levels of soluble α-synuclein protein are lower in DLB and PD, there is no evidence for a corresponding decrease in α-synuclein mRNA levels. This might result from altered translation, or removal of α-synuclein protein from a soluble detectable state, either by turnover or conversion to an insoluble form.
Keywords	Alzheimer disease ; Parkinson disease ; brain ; etiology ; gene duplication ; humans ; idiopathic diseases ; patients ; quantitative polymerase chain reaction
Language	English
Dates of publication	2012-0612
Size	p. 71-80.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2012.04.018
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Identification of valid reference genes for the normalization of RT qPCR gene expression data in human brain tissue

Ravid Rivka / Irvine G Brent / Murphy Suzanne / Quinn Joseph G / Brockbank Simon / Coulson David TR / Johnston Janet A

BMC Molecular Biology, Vol 9, Iss 1, p

2008 Volume 46

Abstract: Abstract Background Studies of gene expression in post mortem human brain can contribute to understanding of the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies ( ... ...

Abstract	Abstract Background Studies of gene expression in post mortem human brain can contribute to understanding of the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Quantitative real-time PCR (RT qPCR) is often used to analyse gene expression. The validity of results obtained using RT qPCR is reliant on accurate data normalization. Reference genes are generally used to normalize RT qPCR data. Given that expression of some commonly used reference genes is altered in certain conditions, this study aimed to establish which reference genes were stably expressed in post mortem brain tissue from individuals with AD, PD or DLB. Results The present study investigated the expression stability of 8 candidate reference genes, (ubiquitin C [UBC], tyrosine-3-monooxygenase [YWHAZ], RNA polymerase II polypeptide [RP II], hydroxymethylbilane synthase [HMBS], TATA box binding protein [TBP], β-2-microglobulin [B2M], glyceraldehyde-3-phosphate dehydrogenase [GAPDH], and succinate dehydrogenase complex-subunit A, [SDHA]) in cerebellum and medial temporal gyrus of 6 AD, 6 PD, 6 DLB subjects, along with 5 matched controls using RT qPCR (TaqMan ® Gene Expression Assays). Gene expression stability was analysed using geNorm to rank the candidate genes in order of decreasing stability in each disease group. The optimal number of genes recommended for accurate data normalization in each disease state was determined by pairwise variation analysis. Conclusion This study identified validated sets of mRNAs which would be appropriate for the normalization of RT qPCR data when studying gene expression in brain tissue of AD, PD, DLB and control subjects.
Keywords	Biology (General) ; QH301-705.5 ; Science ; Q ; DOAJ:Biology ; DOAJ:Biology and Life Sciences ; Genetics ; QH426-470 ; Cytology ; QH573-671
Language	English
Publishing date	2008-05-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: BACE1 mRNA expression in Alzheimer's disease postmortem brain tissue.

Coulson, David T R / Beyer, Nancy / Quinn, Joe G / Brockbank, Simon / Hellemans, Jan / Irvine, G Brent / Ravid, Rivka / Johnston, Janet A

Journal of Alzheimer's disease : JAD

2010 Volume 22, Issue 4, Page(s) 1111–1122

Abstract: β-site AβPP cleaving enzyme 1 (BACE1) catalyses the rate-limiting step for production of amyloid-β (Aβ) peptides, involved in the pathological cascade underlying Alzheimer's disease (AD). Elevated BACE1 protein levels and activity have been reported in ... ...

Abstract	β-site AβPP cleaving enzyme 1 (BACE1) catalyses the rate-limiting step for production of amyloid-β (Aβ) peptides, involved in the pathological cascade underlying Alzheimer's disease (AD). Elevated BACE1 protein levels and activity have been reported in AD postmortem brains. Our study explored whether this was due to elevated BACE1 mRNA expression. RNA was prepared from five brain regions in three study groups: controls, individuals with AD, and another neurodegenerative disease group affected by either Parkinson's disease (PD) or dementia with Lewy bodies (DLB). BACE1 mRNA levels were measured using quantitative realtime PCR (qPCR) and analyzed by qbasePLUS using validated stably-expressed reference genes. Expression of glial and neuronal markers (glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE), respectively) were also analyzed to quantify the changing activities of these cell populations in the tissue. BACE1 mRNA levels were significantly elevated in medial temporal and superior parietal gyri, compared to the PD/DLB and/or control groups. Superior frontal gryus BACE1 mRNA levels were significantly increased in the PD/DLB group, compared to AD and control groups. For the AD group, BACE1 mRNA changes were analyzed in the context of the reduced NSE mRNA, and strongly increased GFAP mRNA levels apparent as AD progressed (indicated by Braak stage). This analysis suggested that increased BACE1 mRNA expression in remaining neuronal cells may contribute to the increased BACE1 protein levels and activity found in brain regions affected by AD.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Aspartic Acid Endopeptidases/genetics ; Aspartic Acid Endopeptidases/metabolism ; Brain/metabolism ; Female ; Glial Fibrillary Acidic Protein/genetics ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Lewy Body Disease/genetics ; Lewy Body Disease/metabolism ; Male ; Middle Aged ; Neuroglia/metabolism ; Neurons/metabolism ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Phosphopyruvate Hydratase/genetics ; Phosphopyruvate Hydratase/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction
Chemical Substances	Glial Fibrillary Acidic Protein ; RNA, Messenger ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; BACE1 protein, human (EC 3.4.23.46) ; Phosphopyruvate Hydratase (EC 4.2.1.11)
Language	English
Publishing date	2010
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-2010-101254
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Article ; Online: Plasma clusterin levels and the rs11136000 genotype in individuals with mild cognitive impairment and Alzheimer's disease.

Mullan, Gemma M / McEneny, Jane / Fuchs, Marc / McMaster, Cyril / Todd, Stephen / McGuinness, Bernadette / Henry, Mark / Passmore, A Peter / Young, Ian S / Johnston, Janet A

Current Alzheimer research

2013 Volume 10, Issue 9, Page(s) 973–978

Abstract: Aim: Substantial evidence links atherosclerosis and Alzheimer's disease (AD). Apolipoproteins, such as apolipoprotein E, have a causal relationship with both diseases. The rs11136000 SNP within the CLU gene, which encodes clusterin (apolipoprotein J), ... ...

Abstract	Aim: Substantial evidence links atherosclerosis and Alzheimer's disease (AD). Apolipoproteins, such as apolipoprotein E, have a causal relationship with both diseases. The rs11136000 SNP within the CLU gene, which encodes clusterin (apolipoprotein J), is also associated with increased AD risk. The aim of this study was to investigate the relationship between plasma clusterin and the rs11136000 genotype in mild cognitive impairment (MCI) and AD. Methods: Plasma and DNA samples were collected from control, MCI and AD subjects (n=142, 111, 154, respectively). Plasma clusterin was determined by ELISA and DNA samples were genotyped for rs11136000 by TaqMan assay. Results: Plasma clusterin levels were higher in MCI and AD subjects vs. controls (222.3 ± 61.3 and 193.6 ± 58.2 vs. 178.6 ± 52.3 μg/ml, respectively; p<0.001 for both comparisons), and in MCI vs. AD (p<0.05). Plasma clusterin was not influenced by genotype in the MCI and AD subjects, although in control subjects plasma clusterin was lower in the TT vs. TC genotypes (157.6 ± 53.4 vs. 188.6 ± 30.5 μg/ml; p<0.05). Conclusion: This study examined control, MCI and AD subjects, identifying for the first time that plasma clusterin levels were influenced, not only by the presence of AD, but also the transitional stage of MCI, while rs11136000 genotype only influenced plasma clusterin levels in the control group. The increase in plasma clusterin in MCI and AD subjects may occur in response to the disease process and would be predicted to increase binding capacity for amyloid-beta peptides in plasma, enhancing their removal from the brain.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/blood ; Alzheimer Disease/genetics ; Clusterin/blood ; Clusterin/genetics ; Cognitive Dysfunction/blood ; Cognitive Dysfunction/genetics ; Disease Progression ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide
Chemical Substances	Clusterin
Language	English
Publishing date	2013-10-09
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205170-3
ISSN	1875-5828 ; 1567-2050
ISSN (online)	1875-5828
ISSN	1567-2050
DOI	10.2174/15672050113106660162
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Article ; Online: Proteasome-mediated effects on amyloid precursor protein processing at the gamma-secretase site.

Flood, Fiona / Murphy, Suzanne / Cowburn, Richard F / Lannfelt, Lars / Walker, Brian / Johnston, Janet A

The Biochemical journal

2005 Volume 385, Issue Pt 2, Page(s) 545–550

Abstract: Abeta (beta-amyloid) peptides are found aggregated in the cortical amyloid plaques associated with Alzheimer's disease neuropathology. Inhibition of the proteasome alters the amount of Abeta produced from APP (amyloid precursor protein) by various cell ... ...

Abstract	Abeta (beta-amyloid) peptides are found aggregated in the cortical amyloid plaques associated with Alzheimer's disease neuropathology. Inhibition of the proteasome alters the amount of Abeta produced from APP (amyloid precursor protein) by various cell lines in vitro. Proteasome activity is altered during aging, a major risk factor for Alzheimer's disease. In the present study, a human neuroblastoma cell line expressing the C-terminal 100 residues of APP (SH-SY5Y-SPA4CT) was used to determine the effect of proteasome inhibition, by lactacystin and Bz-LLL-COCHO (benzoyl-Leu-Leu-Leu-glyoxal), on APP processing at the gamma-secretase site. Proteasome inhibition caused a significant increase in Abeta peptide levels in medium conditioned by SH-SY5Y-SPA4CT cells, and was also associated with increased cell death. APP is a substrate of the apoptosis-associated caspase 3 protease, and we therefore investigated whether the increased Abeta levels could reflect caspase activation. We report that caspase activation was not required for proteasome-inhibitor-mediated effects on APP (SPA4CT) processing. Cleavage of Ac-DEVD-AMC (N-acetyl-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin), a caspase substrate, was reduced following exposure of SH-SY5Y-SPA4CT cells to lactacystin, and co-treatment of cells with lactacystin and a caspase inhibitor [Z-DEVD-FMK (benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone)] resulted in higher Abeta levels in medium, augmenting those seen with lactacystin alone. This study indicated that proteasome inhibition could increase APP processing specifically at the gamma-secretase site, and increase release of Abeta, in the absence of caspase activation. This indicates that the decline in proteasome function associated with aging would contribute to increased Abeta levels.
MeSH term(s)	Acetylcysteine/analogs & derivatives ; Acetylcysteine/pharmacology ; Amyloid Precursor Protein Secretases ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Peptides/pharmacology ; Amyloid beta-Protein Precursor/metabolism ; Aspartic Acid Endopeptidases ; Caspase Inhibitors ; Caspases/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Culture Media/chemistry ; Endopeptidases/metabolism ; Humans ; Multienzyme Complexes ; Neuroblastoma/metabolism ; Neuroblastoma/pathology ; Peptide Hydrolases/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Caspase Inhibitors ; Culture Media ; Multienzyme Complexes ; Proteasome Inhibitors ; lactacystin (133343-34-7) ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Endopeptidases (EC 3.4.-) ; Peptide Hydrolases (EC 3.4.-) ; Caspases (EC 3.4.22.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; BACE1 protein, human (EC 3.4.23.46) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; DEVDase (EC 3.4.99.-) ; Acetylcysteine (WYQ7N0BPYC)
Language	English
Publishing date	2005-01-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20041145
Database	MEDical Literature Analysis and Retrieval System OnLINE

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