Amyloid Precursor Protein Revisited

Guo, Qinxi; Li, Hongmei; Gaddam, Samson Sujit Kumar; Justice, Nicholas J.; Robertson, Claudia S.; Zheng, Hui

doi:10.1074/jbc.m111.315051

Cited by 78 publications

(55 citation statements)

References 48 publications

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“…However, a C‐terminal monoclonal rabbit antibody has been developed (Y188, Epitomics) and is able to specifically recognize human and murine APP in immunocytochemistry and immunohistochemistry (Guo et al ., 2012). We tested both novel rat antibodies for their ability to detect endogenous hAPP in HEK293T cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Hence, we are convinced that both antibodies can be used to study trafficking, function and expression of the hAPP protein in patient fibroblasts and induced pluripotent stem cells (iPS) derived thereof as well as in neurons of AD patients and healthy individuals to study the behaviour or localization of normal or mutant hAPP via microscopy (Israel et al ., 2012; Shi et al ., 2012; Kondo et al ., 2013). Currently, to the best of our knowledge, there is only one commercial APP antibody called Y188 directed towards an epitope of the APP cytoplasmic domain which has been shown to be specific for APP in immunocytochemistry while many other tested antibodies like 22C11 are not (Guo et al ., 2012). However, Y188 cannot discriminate human and murine APP and binds to the intracellular domain which prohibits staining of vital cells.…”

Section: Discussionmentioning

confidence: 99%

“…Until now no antibodies have been available which could convincingly discriminate ectopically expressed human from endogenous murine APP in immunocytochemistry and immunohistochemistry to detect these differences. In a study that compared several APP and Aβ antibodies (4G8, 22C11, Y188 and others) for their specificity in immunocytochemistry between wild‐type and APP knockout neurons, only the antibody Y188 specifically recognized APP (Guo et al ., 2012). However, this antibody detects both overexpressed human and endogenous murine APP, making it impossible to distinguish among APP of different species.…”

Section: Introductionmentioning

confidence: 99%

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Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

et al. 2016

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SummaryAlzheimer's disease (AD) is histopathologically characterized by neurodegeneration, the formation of intracellular neurofibrillary tangles and extracellular Aβ deposits that derive from proteolytic processing of the amyloid precursor protein (APP). As rodents do not normally develop Aβ pathology, various transgenic animal models of AD were designed to overexpress human APP with mutations favouring its amyloidogenic processing. However, these mouse models display tremendous differences in the spatial and temporal appearance of Aβ deposits, synaptic dysfunction, neurodegeneration and the manifestation of learning deficits which may be caused by age‐related and brain region‐specific differences in APP transgene levels. Consequentially, a comparative temporal and regional analysis of the pathological effects of Aβ in mouse brains is difficult complicating the validation of therapeutic AD treatment strategies in different mouse models. To date, no antibodies are available that properly discriminate endogenous rodent and transgenic human APP in brains of APP‐transgenic animals. Here, we developed and characterized rat monoclonal antibodies by immunohistochemistry and Western blot that detect human but not murine APP in brains of three APP‐transgenic mouse and one APP‐transgenic rat model. We observed remarkable differences in expression levels and brain region‐specific expression of human APP among the investigated transgenic mouse lines. This may explain the differences between APP‐transgenic models mentioned above. Furthermore, we provide compelling evidence that our new antibodies specifically detect endogenous human APP in immunocytochemistry, FACS and immunoprecipitation. Hence, we propose these antibodies as standard tool for monitoring expression of endogenous or transfected APP in human cells and APP expression in transgenic animals.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

et al. 2016

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“…Quantification of endogenous APP levels in the brain is confounded by the fact that some commercially available antibodies recognize not only full-length APP but also APP cleavage products and/or other protein fragments (Guo et al, 2012). In addition, antibodies may cross-react with the highly homologous APLPs, which further limits antibody specificity (Slunt et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Since APP is alternatively spliced into three major isoforms (Kang et al, 1987; Tanzi et al, 1988; Sisodia et al, 1993; Rohan de Silva et al, 1997), i.e., APP-770, APP-695 and APP-751, assays detecting all major isoforms were employed. Furthermore, we used an antibody for western blotting, which is highly specific for APP and does not show staining on APP −/− brain tissue (Guo et al, 2012) to quantify APP levels and to study its cellular distribution. The selection of the antibody appeared to be especially important, since some antibodies show unspecific background staining on tissue sections and may cross-react with APP-related proteins, such as the APP-like-proteins 1 or 2 (Anliker and Müller, 2006; Kaden et al, 2012; Müller and Zheng, 2012).…”

Section: Introductionmentioning

confidence: 99%

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

Turco

Paul

Schlaudraff

et al. 2016

Front. Mol. Neurosci.

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The physiological role of amyloid precursor protein (APP) has been extensively investigated in the rodent hippocampus. Evidence suggests that APP plays a role in synaptic plasticity, dendritic and spine morphogenesis, neuroprotection and—at the behavioral level—hippocampus-dependent forms of learning and memory. Intriguingly, however, studies focusing on the role of APP in synaptic plasticity have reported diverging results and considerable differences in effect size between the dentate gyrus (DG) and area CA1 of the mouse hippocampus. We speculated that regional differences in APP expression could underlie these discrepancies and studied the expression of APP in both regions using immunostaining, in situ hybridization (ISH), and laser microdissection (LMD) in combination with quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting. In sum, our results show that APP is approximately 1.7-fold higher expressed in pyramidal cells of Ammon’s horn than in granule cells of the DG. This regional difference in APP expression may explain why loss-of-function approaches using APP-deficient mice revealed a role for APP in Hebbian plasticity in area CA1, whereas this could not be shown in the DG of the same APP mutants.

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Copper signaling in the mammalian nervous system: Synaptic effects

Gaier

Eipper

Mains

2012

J of Neuroscience Research

179

151

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Copper (Cu) is an essential metal present at high levels in the CNS. Its role as a co-factor in mitochondrial ATP production and in other essential cuproenzymes is well defined. Menkes and Wilson’s diseases are severe neurodegenerative conditions that demonstrate the importance of Cu transport into the secretory pathway. Brain levels of Cu, which is almost entirely protein bound, exceed extracellular levels by more than a hundred-fold. Cu stored in the secretory pathway is released in a Ca2+-dependent manner and can transiently reach concentrations over 100 µM at synapses. The ability of low µM levels of Cu to bind to and modulate the function of γ-aminobutyric acid type A (GABAA) receptors, N-methyl-D-aspartate (NMDA) receptors and voltage-gated Ca2+ channels contributes to its effects on synaptic transmission. Cu also binds to amyloid precursor protein and prion protein; both proteins are found at synapses and brain Cu homeostasis is disrupted in mice lacking either protein. Especially intriguing is the ability of Cu to affect AMP-activated protein kinase (AMPK), a monitor of cellular energy status. Despite this, few investigators have examined the direct effects of Cu on synaptic transmission and plasticity. Although the variability of results demonstrates complex influences of Cu that are highly method-sensitive, these studies nevertheless strongly support important roles for endogenous Cu and new roles for Cu-binding proteins in synaptic function/plasticity and behavior. Further study of the many roles of Cu in nervous system function will reveal targets for intervention in other diseases in which Cu homeostasis is disrupted.

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Amyloid Precursor Protein Revisited

Cited by 78 publications

References 48 publications

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

Copper signaling in the mammalian nervous system: Synaptic effects

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