The beta APP717 Alzheimer mutation increases the percentage of plasma amyloid-beta protein ending at A beta 42(43)

Kosaka, Toshiyuki; Imagawa, Masaki; Seki, Koji; Arai, Hiroyuki; Sasaki, Hironobu; Tsuji, Shoji; Asami-Odaka, Asano; Fukushima, Tsuyoshi; Imai, Kazuhiro; Iwatsubo, Takeshi

doi:10.1212/wnl.48.3.741

Cited by 101 publications

(71 citation statements)

References 6 publications

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“…Purified A␤40 (Bachem, King of Prussia, PA) was used as standard. The sensitivity of this ELISA assay is 1 pM A␤, and it is not affected by serum and plasma proteins because of the high affinity of the antibodies (Scheuner et al, 1996;Kosaka et al, 1997;Fukumoto et al, 2003). Cells were checked for consistent expression of constructs using Western blotting as described above.…”

Section: Methodsmentioning

confidence: 99%

Interaction of the Cytosolic Domains of sorLA/LR11 with the Amyloid Precursor Protein (APP) and β-Secretase β-Site APP-Cleaving Enzyme

Spoelgen¹,

Arnim²,

Thomas³

et al. 2006

J. Neurosci.

163

135

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sorLA is a recently identified neuronal receptor for amyloid precursor protein (APP) that is known to interact with APP and affect its intracellular transport and processing. Decreased levels of sorLA in the brain of Alzheimer's disease (AD) patients and elevated levels of amyloid-␤ peptide (A␤) in sorLA-deficient mice point to the importance of the receptor in this neurodegenerative disorder. We analyzed APP cleavage in an APP-shedding assay and found that both sorLA and, surprisingly, a sorLA tail construct inhibited APP cleavage in a ␤-site APP-cleaving enzyme (BACE)-dependent manner. In line with this finding, sorLA and the sorLA tail significantly reduced secreted A␤ levels when BACE was overexpressed, suggesting that sorLA influences ␤-cleavage. To understand the effect of sorLA on APP cleavage by BACE, we analyzed whether sorLA interacts with APP and/or BACE. Because both full-length sorLA and sorLA C-terminal tail constructs were functionally relevant for APP processing, we analyzed sorLA-APP for a potential cytoplasmatic interaction domain. sorLA and C99 coimmunoprecipitated, pointing toward the existence of a new cytoplasmatic interaction site between sorLA and APP. Moreover, sorLA and BACE also coimmunoprecipitate. Thus, sorLA interacts both with BACE and APP and might therefore directly affect BACE-APP complex formation. To test whether sorLA impacts BACE-APP interactions, we used a fluorescence resonance energy transfer assay to evaluate BACE-APP interactions in cells. We discovered that sorLA significantly reduced BACE-APP interactions in Golgi. We postulate that sorLA acts as a trafficking receptor that prevents BACE-APP interactions and hence BACE cleavage of APP.

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Section: Methodsmentioning

confidence: 99%

Interaction of the Cytosolic Domains of sorLA/LR11 with the Amyloid Precursor Protein (APP) and β-Secretase β-Site APP-Cleaving Enzyme

Spoelgen¹,

Arnim²,

Thomas³

et al. 2006

J. Neurosci.

163

135

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“…Several genes that are involved in Aβ generation have been identified [9,21]. Mutations in APP and in Presenilins 1 and 2 and the presence of the apolipoprotein E (APOE) ε4 allele are associated with increased accumulation of Aβ in the brain and increased risk for AD [10,12,16], yet the mechanisms through which the genetic variants act are still uncertain. …”

mentioning

confidence: 99%

Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome

Lee

Chulikavit

Pang

et al. 2007

Neuroscience Letters

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Recent reports have suggested that variants in the sortilin-related receptor gene (SORL1) increase the risk of late onset Alzheimer's disease (AD) in Northern European, Hispanic, African-American and Isreali-Arab populations. SORL1 directs trafficking of amyloid precursor protein (APP) and under-expression of SORL1 may lead to over-expression of β amyloid peptides. Adults with Down syndrome (DS) over-express APP and have early onset and high risk for AD. We investigated the relation of seven variants in the gene for SORL1 to age at onset and risk for AD among 208 adults with DS, 45-70 years of age at baseline. Participants were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Homozygosity for the minor T allele in rs556349 and for the minor C allele in rs536360 was associated with later age at onset and reduced risk of AD (HR= 0.26, and HR= 0.40, respectively). Mean age at onset was approximately four years later in individuals who were homozygous for those alleles compared with those who had at least one major allele. These findings indicate a modest association of variants in SORL1 with AD. In addition, we did not observe the same alleles to be associated with AD compared with earlier studies, suggesting that these SNPs are in linkage disequilibrium (LD) with the putative functional variants or that expression of the SORL1 gene and hence its interaction with APP might be modified by the extremely high levels of APP characteristic of Down syndrome. Thus, further studies are needed to identify functional variants that influence risk for AD in this uniquely vulnerable population. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Deposition of β amyloid peptides (Aβ) is a primary event in the pathogenesis of AD. Amyloid peptides Aβ40 and Aβ42, the two major species of amyloid β, are generated from a larger membrane bound protein, the amyloid precursor protein (APP), located on chromosome 21, by sequential proteolytic cleavage by β and γ secretases [6,8,19]. Several genes that are involved in Aβ generation have been identified [9,21]. Mutations in APP and in Presenilins 1 and 2 and the presence of the apolipoprotein E (APOE) ε4 allele are associated with increased accumulation of Aβ in the brain and increased risk for AD [10,12,16], yet the mechanisms through which the genetic variants act are still uncertain. NIH Public AccessRecent reports hav...

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“…[13][14][15]21,22 Although one study showed an increase in Aβ levels, 22 the majority of studies have found no significant differences between AD and control cases. 13,14,16,17,23 Increased Aβ40 and sometimes Aβ42 correlate strongly with age. 15,23 A broad overlap in plasma Aβ levels between AD and control cases suggests that plasma Aβ cannot reliably differentiate sporadic AD from control cases.…”

Section: Blood Biomarkers For Alzheimer's Disease Blood Biomarkers Fomentioning

confidence: 99%

“…The plasma total Aβ or Aβ42 was increased in familial AD with presenilin or APP mutations 16,17 and in Down's syndrome with APP triplication, 18 which raises the possibility that sporadic AD may also be associated with detectable and diagnostic changes in Aβ plasma levels. Animal models suggest that Aβ can pass between cerebrospinal fluid (CSF) and plasma compartments, 19,20 but this has yet to be confirmed in humans.…”

Section: Amyloid β-Proteinmentioning

confidence: 99%

Blood Biomarkers for Alzheimer’s Disease

Winblad¹,

Lönneborg²

2008

European Neurological Review

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Alzheimer's disease (AD) is a multifactorial and heterogeneous disease in both its clinical and histopathological appearance. In more than 99% of cases the cause of the disease is not understood. Independent of its cause, AD is clinically characterised by a developing dementia and histopathologically characterised by neuronal degeneration.Although the presence of neurofibrillary tangles (NFTs) and neurotic The development of biomarkers for AD is challenging as it is complicated by several factors. In addition to the variability in clinical features and multiple molecular aetiologies, the development of AD biomarkers is burdened with a diagnostic imprecision as confirmation of the disease preferentially has to await a post mortem histopathological examination.The long asymptomatic prodromal stages, rates of progression and complex disease genetics complicate the situation further. In this article we will review the current developments in the field of biomarkers for the detection of AD in blood. Single-component BiomarkersThe physiology of the blood-brain barrier limits potential biomarkers that are closely associated to brain pathophysiology to small molecules, lipophilic molecules and molecules with specific transporters. 12 Brainderived proteins and metabolites that pass into the plasma will also become markedly diluted in a biochemically complex medium. 12 Moreover, it is not known whether there are any direct pathophysiological processes associated with AD in blood cells. The traditional approach of using one or a few closely related molecules as a biomarker, a single-component biomarker, in plasma, serum or blood has been utilised since the late 1990s. [13][14][15] However, their usefulness has been limited, mainly due to discrepant results between studies. Amyloid β-proteinAβ can be detected in plasma and is thus a compelling candidate biomarker for AD. The plasma total Aβ or Aβ42 was increased in familial AD with presenilin or APP mutations 16,17 and in Down's syndrome with APP triplication, 18 which raises the possibility that sporadic AD may also be associated with detectable and diagnostic changes in Aβ plasma levels. Animal models suggest that Aβ can pass between cerebrospinal fluid (CSF) and plasma compartments, 19,20 but this has yet to be confirmed in humans. APP is also produced by platelets and is, therefore, an alternative source for the APP and Aβ pools found in plasma.

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The beta APP717 Alzheimer mutation increases the percentage of plasma amyloid-beta protein ending at A beta 42(43)

Cited by 101 publications

References 6 publications

Interaction of the Cytosolic Domains of sorLA/LR11 with the Amyloid Precursor Protein (APP) and β-Secretase β-Site APP-Cleaving Enzyme

Interaction of the Cytosolic Domains of sorLA/LR11 with the Amyloid Precursor Protein (APP) and β-Secretase β-Site APP-Cleaving Enzyme

Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome

Blood Biomarkers for Alzheimer’s Disease

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